Hepatic Lipid Metabolism and Herbal Impacts on Non-Alcoholic Fatty Liver Disease

Jia Xiao; Jiteng Wang; Tao Han; Emily C Liong; Feiyue Xing; George L Tipoe

doi:10.4172/2324-9323.1000122

Review Article, J Food Nutr Disord Vol: 2 Issue: 4

Hepatic Lipid Metabolism and Herbal Impacts on Non-Alcoholic Fatty Liver Disease

Jia Xiao^1,3, Jiteng Wang², Tao Han², Emily C Liong³, Feiyue Xing¹ and George L Tipoe^3,4*
¹Institute of Tissue Transplantation and Immunology, Department of Immunobiology, Jinan University, Guangzhou, China
²Fisheries College of Zhejiang Ocean University, Zhoushan, China
³Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
⁴Brain Hormone Healthy Aging Centre, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
Corresponding author : Dr. George L Tipoe Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China Tel: (852) 2819-9185; Fax: (852) 2817-0857 E-mail: tgeorge@hku.hk
Received: June 11, 2013 Accepted: October 11, 2013 Published: October 16, 2013
Citation: Xiao J, Wang J, Han T, Liong EC, Xing F, et al. (2013) Hepatic Lipid Metabolism and Herbal Impacts on Non-Alcoholic Fatty Liver Disease. J Food Nutr Disor 2:4. doi:10.4172/2324-9323.1000122

Abstract

Hepatic Lipid Metabolism and Herbal Impacts on Non-Alcoholic Fatty Liver Disease

Dysregulation of hepatic lipid metabolism is one of the most important causal events of non-alcoholic fatty liver disease(NAFLD). The balance between lipogenesis and lipolysis achieved through pharmacological intervention is proven to effectively ameliorate NAFLD induced liver injury in both pre-clinical studies and clinical trials. In recent years, treatment of NAFLD using herbal derivatives receives wide attention because they effectively restore normal functions on several key pathological events during NAFLD progression with minimal adverse effects when taken in a suggested reasonable dose.

Download PDF

Introduction
Up to date, non-alcoholic fatty liver disease (NAFLD) is a significant global problem which influences one third of the adult population in affluent countries and obese people [1-3]. It is a kind of hepatic- and metabolic-disorder disease not attributed to the abuse of alcohol (≤ 30 g/day for men, ≤ 20 g/day for women) [4]. NAFLD is considered as an independent predictor of insulin resistance [5], the metabolic syndrome [6], and cardiovascular diseases [7]. Moreover, a certain percentage of NAFLD patients may progress to late-stage liver diseases, including cirrhosis and hepatocellular carcinoma [8]. Therefore, elucidating the pathogenic mechanisms of NAFLD is crucial for the clinical control and therapy of this liver disease. The most updated pathological model for NAFLD is the “multiple parallel hit” model in which the dysregulation of lipid metabolism and insulin resistance are considered as the “first-hits” to the liver. Then other typical features of clinical NAFLD, such as oxidative stress, inflammation, chemoattraction, necrosis, fibrosis, and apoptosis, are “parallel multiple hits” subsequently [9]. Recent studies also pointed out that the “downstream” events may regulate or influence the “upstream” event lipid metabolism, forming a positive or negative feedback loop during the development of NAFLD. For example, hepatic autophagy is found to regulate the lipid metabolism and mitochondrial conformation, demonstrating two novel physiological activities namely “lipophagy” and “mitophagy”, respectively [10,11]. As the direct cause of steatosis, lipoperoxidative stress and inflammation, lipid accumulation results from an imbalance between lipid availability (hepatic lipogenic pathways) and lipid disposal (hepatic lipolytic pathways) in a dynamic process [12]. Besides conventional diagnostic means, there are several novel biomarkers which have been identified based on the unbalance between apoptosis/ anti-apoptosis process [13,14], low grade chronic inflammation [15,16], contribution of adipose tissue [17], and the key role of the liver-spleen axis [18]. For example, it is found that anti-apoptotic serum marker Bcl-2 [13] and apoptosis-related cytochrome c [14] can be used as diagnostic indicators in overweight/obese patients with NAFLD. In addition, interleukin-6 (IL-6) is highly specific in confirming the absence of NASH at normal values, which can also be used as a novel biomarker [19]. Until now, there is no direct and effective therapy for NAFLD. Current therapeutic strategies include two major categories: (1) lifestyle interventions (include weight reduction, dietary modification and physical exercise) and (2) pharmaceutical therapies [20]. Besides regular pharmaceutical intervention (e.g. insulin sensitizer and lipid lowering agent), applying herbal derivatives as antioxidant and lipid-balancing agents received massive attention in recent years. Although the underlying mechanisms of the beneficial effects warrant further investigation, herbal derivatives hold several advantages in the daily prevention or treatment of NAFLD. They are widely available around the world and with low or minimal side-effects. Some of them have been extensively studied in modern basic and clinical studies [21]. Therefore, in the present review, the lipid accumulation pathways during NAFLD is described firstly, followed by the current advances in the beneficial impacts of herbal derivatives on the lipid regulation pathways. Several derivatives, which have been extensively investigated for their lipidregulating and anti-NAFLD mechanisms in recent years, will also be highlighted in this review.
Hepatic Lipid Metabolism During NAFLD Pathogenesis
Hepatic lipolytic pathways
In the pathogenesis of NAFLD, several hepatic fatty acids (FA) pathways are involved. The mitochondrial and peroxisomal β-oxidations are the major processes that metabolize FA [22,23]. The third pathway is the ω-oxidation which occurs in the endoplasmic reticulum (microsomes) through the actions of cytochrome P450 4A (CYP4A) [24,25]. Mitochondrial β-oxidation is the primary pathway that metabolizes short-chain (< C₈), medium-chain (C₈- C₁₂), and long-chain (C₁₂–C₂₀) FA, in order to provide energy to other cellular activities. During this process, electrons are transferred from fatty acyl-CoA to flavin-adenine dinucleotide and is oxidized to nicotinamideadenine dinucleotide (NAD+), resulting in reduced form of fatty acyl-CoA and donates electrons to drive ATP synthesis [26]. Mitochondrial β-oxidation is regulated by carnitine palmitoyltransferase-I (CPT-I). The carnitine concentration and the negative regulator of CPT-I (e.g. malonyl-CoA) modulate the function of CPT-I [27]. CPT-I is integrated on the outer mitochondrial membrane and catalyzes the formation of acylcarnitine molecules via the action of CPT-II, a peripheral protein of the inner mitochondrial membrane. The function of malonyl-CoA on CPT-I is to prevent the simultaneous oxidation and synthesis of FA in the liver [28]. Deficiency of hepatic CPT-I in patients exhibits hypoketotic hypoglycemia beginning in early childhood which is usually associated with fasting or illness [29]. Unlike mitochondrial β-oxidation, peroxisomal β-oxidation is mainly responsible for the metabolism of very long chain FA (>C20), which is less abundant and relatively more toxic and biologically active. In peroxisomes, the first step of β-oxidation is catalyzed by acyl-CoA oxidase to form H₂O₂ rather than reduced NAD+. Because there is no electron transport chain in peroxisome, peroxisomal β-oxidation produces less ATPenergy than mitochondrial β-oxidation does [30]. When peroxisomal fatty acyl-CoA oxidase is deficient, mice show high serum level of very long chain FA (>C22) with growth retardations, steatohepatitis and even hepatocellular carcinoma, implicating the significant functions of peroxisomal fatty acyl-CoA oxidase in the pathogenesis of NAFLD [31]. Another important oxidation pathway for the metabolism of very long chain FA is the CYP4A-dependent ω-oxidation system, which metabolizes very long chain FA to long chain dicarboxylic acids. They are taken up by the peroxisomes and then oxidized to FA that can be utilized by the mitochondria. Therefore, when over-load of lipid in the liver occurs (e.g. steatosis), mitochondrial, peroxisomal and microsomal oxidation are activated cooperatively to maintain the hepatic lipid homeostasis [32].
Very low density lipoprotein (VLDL) is a kind of lipoprotein synthesized in the liver triglycerides (TG), cholesterol and apolipoproteins. The mechanism of VLDL synthesis and secretion in the liver is well-documented. Apoprotein B protein (primarily apoB100) is the key component which limits the overall production rate of VLDL in the rough endoplasmic reticulum. In the smooth endoplasmic reticulum, other lipid components are added by the microsomal triacylglycerol transfer protein (MTP) to apoB. When carried to the Golgi apparatus, apoB is glycosylated and then it migrates to the sinusoidal membrane of the hepatocyte to be released to the circulation [33]. When MTP is blocked in mice, the assembly and secretion of VLDL and chylomicrons are inhibited, leading to the occurrence of steatosis [34]. Recent clinical studies demonstrate that hepatic TG and VLDL secretion rate is increased in NAFLD. But the increase of hepatic TG export is not adequate to normalize the intrahepatic triglyceride (IHTG) content [35]. Genetic defects of apoB-containing lipoprotein assembly lead to hepatic fat accumulation (e.g. human abetalipoproteinemia), in which neither intestinal nor hepatic apoB lipoproteins are found in the plasma [36]. In addition, functional polymorphism in the promoter of MTP (i.e. -493 G/T) independently enhances the vulnerability of human to fatty liver diseases [37,38]. Diacylglycerol acyltransferases (DGATs, including DGAT1 and DGAT2) are important regulatory enzymes for the secretion of apoB protein during the development of steatosis. DGAT1 promotes the secretion of VLDL from the lumen of the endoplasmic reticulum. Therefore, over-expression of DGAT1 in mice often predicts the increases of VLDL secretion, hepatic TG concentration and gonadal fat. Over-expression of DGAT2 results in significant increase of hepatic fat content, since DGAT2 plays a key role in cytosolic lipid accumulation [39]. Deficiency study of DGAT2 further confirms such observations [40].
Hepatic lipogenic pathways
Hepatic non-esterified fatty acid (NEFA) uptake: Non-esterified fatty acids (NEFA) are taken by the liver from the blood in proportion to their circulating concentration. They can be metabolized from the hydrolysis of complex lipids by lipases either from dietary or endogenous sources, or from the hydrolysis of fatty acid-CoA by thioesterases. In the liver, fatty acid transport protein (FATP) or fatty acid translocase (FAT) and CD36 are important cellular transporters that facilitate the entry of NEFA into the cells. After that, lipids are covalently bound by fatty acid binding protein (FABP) or acyl-CoA synthetases (ACS) expressed in the outer mitochondrial membrane and the microsomes for further metabolism or transcription factor activation in the nucleus [41]. These metabolic pathways are responsible for the maintenance of low intracellular NEFA and FA levels.
A recent study exhibits that the structural integrity of lipid rafts in cell membrane is vital for its lipid uptake [42]. Caveolin proteins (caveolin-1, -2 and -3) are cytoplasmically-oriented integral membrane proteins. They are proven to mediate the uptake of lipids into the cells. Mice with caveolin-1 deficiency are resistant to dietinduced obesity and reduced lipid accumulation in hepatocytes [43,44]. Over-expression of caveolin-3 in diabetic mice is found to improve glucose metabolism and insulin signaling [45].
De novo lipogenesis of FA: The process of de novo synthesis of FA is vital for the hepatic lipid homeostasis. It is tightly controlled and regulated at both hormonal and nutritional levels, because high carbohydrate diet induces while starvation inhibits the de novo synthesis of FA. Furthermore, the degree of de novo synthesis of FA is closely associated with the level of insulin and tissue insulin sensitivity. In healthy human, de novo lipogenesis is only elevated postprandially. However, in NAFLD patients, this process is elevated in fasting conditions without further enhancement after meal [46,47]. At the molecular level, a complicated network including a spectrum of transcription factors and receptors is responsible for the precise regulation of de novo lipogenesis. As a result of hyperinsulinemia and endocannabinoid activation, sterol-regulatory element binding protein-1c (SREBP-1c) is over-expressed during the development of NAFLD. SREBP-1c is an important transcription factor regulating de novo lipogenesis. It has high expressions in the liver, white adipose tissue, adrenal gland and brain. SREBP-1c expression is suppressed during fasting but significantly elevated after the meal (particularly high-fat or high carbohydrate food) by insulin signaling through the phosphoinositide 3-kinase (PI3K)-dependent pathways [48-50]. Glucagon, forkhead box protein O1 (FoxO1) and AMP-activated kinase (AMPK)-dependent pathways are shown to inhibit the activity of SREBP-1c [51-53]. Interestingly, SREBP-1c alone is not enough to induce gene expression in response to carbohydrate since SREBP-1c gene deletion in mice only results in a 50% reduction in FA synthesis [54]. A recently identified transcription factor known as carbohydrate responsive element binding protein (ChREBP) partly filled this gap. In the liver, this factor is activated by glucose and translocated into the nucleus, then it induces the transcription of lipogenic gene through binding to their carbohydrate responsive element in the promoter region [55,56]. Recently, it is found that liver X receptors (LXRs) can directly regulate the activity of ChREBP [57]. When ChREBP is knockdown in ob/ob mice, hepatic lipogenic rates, fat accumulation, plasma TG and NEFA concentrations are significantly declined, leading to the improvement of hyperglycemia and hyperinsulinemia [58]. In response to mitochondrial and peroxisomal β-oxidation, peroxisome proliferator-activated receptors (PPARs) are induced to prevent hepatic triacylglycerol infiltration and to increase the rate of fatty acid catabolism [59,60]. In a methionine- and choline-deficient (MCD) diet-induced NAFLD mice model, treatment with the PPARα agonist Wy-14643 reduced fibrotic steatohepatitis by the reduction of stimuli (e.g. lipid peroxides) and the activation of cells responsible for promotion of hepatic fibrosis [61]. This result is consistent with other reports indicating the anti-inflammatory properties of PPARα, probably through inhibiting IL-6 and cyclooxygenase-2 (COX-2) mediated by nuclear factor-kappa B (NF-κB) [59,62]. PPARγ is also important for the regulation of lipid metabolism, with highest expression in adipose tissue and relatively low level in hepatocytes, stellate cells and macrophages. It promotes FA uptake and insulin sensitivity when there is an increased lipid “influx” in hepatocytes and adipocytes. Liver-specific deletion of PPARγ in db/db mice improves fatty liver but aggravates diabetic phenotypes [63]. In addition, it also increases the plasma level of adiponectin and adiponectin receptor expression in the liver [64,65]. Overall, developing novel PPARγ agonists is promising since PPARγ may reverse a variety of NAFLD features including steatosis, inflammation and fibrosis.
Important hepatic lipogenic enzymes: Some lipogenic enzymes are also thought to be crucial for the induction of steatosis during NAFLD initiation and progression. The first example is acetyl- CoA carboxylases (ACCs, include ACC-1 and ACC-2). In general, ACCs control the rate of de novo lipid synthesis and FA oxidation (e.g. malonyl-CoA) [66]. The tissue distribution of ACC-1 and ACC-2 is different. ACC-1 is mainly expressed in the cytosol of hepatocytes and adipocytes, where ACC-2 is expressed in the heart and skeletal muscle, with relatively lower expression in the liver [67]. In a high-fat diet induced insulin resistance and steatohepatitis rat model with inhibition of ACC-1 and ACC-2 expression using antisense oligonucleotides, the inhibition of ACCs improves insulin sensitivity and reduces the contents of hepatic triacylglycerol, long chain acyl-coenzymes A and diacylglycerol partially through Aktand FoxO1-dependent pathways. ACC-1 inhibition also reduces hepatic lipogenesis while deficiency of ACC-2 has no such effect [68]. Drugs that can inhibit the activity of ACCs have been used in several pre-clinical studies and offered improved metabolic-controlling outcomes. However, due to their non-specific effect on hypothalamus and pancreas, these drugs may also increase food intake and reduce insulin secretion, respectively [69]. Stearoyl-CoA desaturase 1 (SCD1) is another important lipogenic enzyme that mediates the synthesis of monounsaturated long-chain FAs from saturated fatty acyl-CoAs. Since it is predominantly expressed in the liver, SCD1 has become a potential target for treating NAFLD. In mice NAFLD models fed with a high-fat diet or a high carbohydrate diet, knockout of SCD1 improves insulin sensitivity and decreases hepatic liver accumulation via reduced lipogenic activity and increased β-oxidation [70-72]. Recent study also indicates that SCD1 expression is required for carbohydrate-induced adiposity. Its expression in extrahepatic tissues is closely related to the occurrence of obesity and insulin resistance induced by high-fat diet [73]. The role of SCD-1 in cellular pro-inflammatory responses and carcinogenesis are demonstrated in some other recent reports [74,75]. The third lipogenic enzymes that arises emerging attention in NAFLD study is fatty acid synthase (FAS). Its main function is to catalyze the synthesis of palmitate from acetyl-CoA and malonyl-CoA into long-chain saturated fatty acids. In the liver, FAS is regulated by hormones and nutritional state. It is also reversely regulated by the intracellular FA concentration [76]. Very interestingly, knockout of FAS in mice fed with a low fat/high carbohydrate diet for 4 weeks does not protect the mice liver from NAFLD, but exacerbate it due to a reduction of β-oxidation. Such effects are mediated through the activity of a pool of nuclear receptors (e.g., PPARα) which lead to the enhancement of cellular β-oxidation [77].
Impacts of Some Herbal Derivatives on Lipid Metabolism During NAFLD
Lycium barbarum polysaccharide (LBP)
LBP is the polysaccharide portion of the fruit (wolfberry or goji berry) of Lycium barbarum in the family Solanaceae. The usage of wolfberry as a medicinal herb is over 1,000 years in China. Modern biological studies indicate that LBP is the most important part of wolfberry, in terms of beneficial properties against oxidative stress, inflammation, glucose metabolism dysfunction and tumor [78]. In traditional Chinese medicine, the primary protective function of LBP is in the liver and eyes. Therefore, it is interesting to investigate the possible beneficial effects of LBP on the abnormalities or pathological processes in these organs [79]. With alcoholic administration, cotreatment with LBP significantly ameliorated lipid peroxidation and steatosis in the liver [80]. In a carbon tetrachloride (CCl4)-induced acute liver injury model, oral pre-treatment with 1 mg/kg or 10 mg/kg LBP prevents hepatic necrosis, oxidative stress and inflammation, as well as promotes liver regeneration partly through the modulation of NF-κB [81]. In our rat NAFLD model, 8-week feeding with a high-fat diet produces clinical NAFLD symptoms at different levels, including steatosis, fibrosis, inflammation, oxidative stress, apoptosis and autophagy [82,83]. Daily oral feeding with 1 mg/kg LBP significantly improves these NAFLD features without showing obvious influence on healthy rats. For lipid metabolism, in NAFLD rat, the expression of lipogenic genes (SREBP1c and PPARγ2) is up-regulated while the expression of lipolysis genes [adipose triglyceride lipase (ATGL) and adiponectin] is down-regulated, leading to an increase in the circulating level of free fatty acid (FFA) and occurrence of steatosis in the liver [84]. LBP treatment re-balances the expression of both lipogenic and lipolytic genes to correct the FFA level and ameliorate steatosis [85]. However, we are still investigating the effective monomer(s) of LBP that is responsible for its anti-NAFLD properties.
Garlic
Garlic is a species in the onion genus, Allium. It has a history of medicinal use in human for over 7,000 years. Modern science focuses on its therapeutic mechanisms in infection and several diseases, including atherosclerosis, high cholesterol, hypertension, diabetes and cancer [86]. In the liver, it is found that in CCl4- and acetaminophen-induced acute liver injury models, treatment with S-allylmercaptocysteine (SAMC) derived from aged garlic significantly improves typical acute injury features, such as hepatocytes necrosis, oxidative stress, and inflammation [87,88]. Similar to LBP, co-treatment with SAMC alleviated a variety of NAFLD symptoms, from histological changes to apoptosis and autophagy [82]. Increased expression of lipogenic gene (SREBP1c) is observed in the NAFLD rats, whereas the expression of lipolytic gene (adiponectin) is reduced, suggesting an on-going process of hepatic lipid accumulation. Administration of SAMC reverses this process by correcting the expression of these two genes [82]. It is interesting that SAMC treatment also enhances the hepatic autophagy during NAFLD progression. Since autophagy regulates lipid metabolism in the liver (describes as “lipophagy”), autophagy induced by SAMC may play an important role in the reduction of steatosis [10,89]. However, detailed mechanism needs further investigation.
Green tea
It is reported that consumption of green tea improves human health due to its cholesterol reduction and antioxidant properties [90]. In the liver, numerous studies reveal the protective or therapeutic effects of green tea on hepatic disorders. For the treatment of NAFLD, several reports demonstrated that administration of whole green tea extract (GTE) or monomer from green tea alleviates hepatocyte necrosis, fibrosis and other features of NAFLD, particularly hepatic lipid accumulation. In obese mice, 6-week oral GTE administration reduces the body weight of mice. It also ameliorates steatosis through adiponectin-mediated lipid metabolism [91] and the decrease of the release of FA from adipose tissue [92]. GTE down-regulates the expression of SREBP-1c, FAS and SCD-1 in adipose tissue but not in the liver. In addition, the mRNA level of hormone-sensitive lipase and NEFA is also reduced [92]. When co-administered with grape extract and l-carnitine, GTE dramatically reduces high-fat diet induced obesity, with suppressed hyperlipidemia via decreasing the plasma levels of LDL, cholesterol and TG [93]. An 11-month study in mice fed with a high-fat diet containing 0.5% of highly concentrated GTE (92% total polyphenols, 73% total catechins) showed that GTE reduces adipose mass and hepatic TG accumulation due to enhanced β-oxidation [94]. In a human study, acute administration of GTE increases energy expenditure while it decreases the respiratory quotient when compared with the placebo control group treated with equivalent caffeine content [95]. Overall, green tea is a promising herbal supplement against NAFLD with a potent ability in regulating hepatic lipid metabolism [96]. Up to date, epigallocatechin-3-gallate (EGCG) is considered as the main effective monomer that plays major roles in modulating NAFLD-induced hepatic abnormalities [83,97].
Resveratrol
Resveratrol (3,5,40-trihydroxystilbene) is a natural compound presents in grapes and other food products [98]. Previous studies have proven its surprising antioxidant, anti-aging, anti-inflammatory and anti-cancer properties [99-103]. In animal studies, resveratrol is shown to improve insulin sensitivity and lower body weight through regulating AMPK [104], sirtuin-1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator-1-α (PGC-1α) [105], indicating its potential anti-diabetic property. In a palmitateinduced steatosis cell model using hepatoma cell line HepG2, administration of resveratrol significantly reduces the accumulation of cellular TG via up-regulation of FoxO1 and down-regulation of SREBP-1c, and further explores the anti-NAFLD mechanism of resveratrol [106]. These findings are then expanded in a fa/fa Zucker rat model. When reseveratrol is orally taken for 6 weeks, it reduces liver weight, NEFA and triacylglycerol contents without influencing the activities of CPT-Iα and acyl-coenzyme A oxidase (ACO) [107]. Another report points out that in a high fat/sucrose diet (HFS)- induced Wistar rat NAFLD model, resveratrol treatment alleviates steatosis. This effect is mediated by the restoration of LDLR and scavenger receptor class B type I (SR-BI) at both transcriptional and translational levels [108]. In clinical studies, as early as 2008, Sirtris Pharmaceuticals announces that their patent formulation of resveratrol, SRT501, could improve glucose tolerance in type II diabetics in a Phase 1b clinical trial [109], followed by a recent study showing the molecular anti-aging target and mechanisms of resveratrol in the Science Magazine [102]. Overall, the report regarding to the effect of resveratrol on human lipid metabolism is rather limited. If its efficacy can be more thoroughly demonstrated, resveratrol is an attractive choice for the clinical therapeutic application on NAFLD.
Other derivatives
In the past decade, there is a large number of studies investigated the ameliorative effects of herbal derivatives on lipid metabolism during NAFLD progression. For example, silymarin and silibinin are derivatives of plant milk thistle (Silybum marianum). Clinical trials indicate that hepatic steatosis (histological analysis and expression of gamma-glutamyl transpeptidase) and general injury are ameliorated by the treatment of silymarin [110] or the combination of silymarin and vitamin E [111]. In experimental non-alcoholic steatohepatitis mice model, when db/db mice are fed with MCD diet, co-treatment with silibinin improves lipid metabolism in the liver by restoring the expression and activity of SCD-1 [112].
Curcumin is another important herbal derivative extracted from popular Indian spice turmeric, a member of the ginger family (Zingiberaceae). It is found to be effective against the liver injury and lipid accumulation in experimental NAFLD animal models. In obese mice with steatosis, apart from the alleviative effects on hepatic inflammation and oxidative stress, curcumin administration obviously reduces lipid deposition in the liver through the downregulation of SREBP-1c gene expression [113]. In a hepatic stellate cells (HSCs) activation model, curcumin is shown to reduce the abundance of LDLR in activated HSCs and to differentially regulate the expression of SREBP-1 and SREBP-2, leading to the reduced level of cholesterol [114]. This study provides a novel mechanism for the regulatory role of curcumin in hepatic lipid metabolism, making it a good candidate for the prevention hypercholesterolemia-associated hepatic fibrogenesis.
In recent years, the link between coffee consumption and NAFLD receives mass attention since coffee is one of the three major drinks all over the world. In a clinical study, scientists found that high coffee intake is associated with a decrease grade of NAFLD. There is no significant difference in the antioxidant factors measured in this study [115]. In addition, another clinical trial points out that coffee caffeine consumption significantly reduces the risk of fibrosis among NAFLD/ NASH patients [116]. To investigate the underlying mechanism, NASH is firstly established in rats fed with a high-fat/calorie solid diet for 4 weeks. After that, certain amount of decaffeinated coffee or its polyphenols or melanoidins which correspond to approximately 2 cups of filtered coffee or 6 cups of espressoTM coffee for a 70-kg person is treated for another 8 weeks. It is shown that coffee and its polyphenols and melanoidins improve NASH through (1) a reduction in hepatic fat accumulation by increasing β-oxidation; (2) amelioration of hepatic oxidative stress; and (3) reduction in hepatic inflammation via suppressing the expression of pro-inflammatory cytokines [117].
Goshajinkigan (GJ) is an extract from traditional Japanese herbal medicine (Kampo). GJ has been demonstrated to treat patients with numbness, melosalgia, and back pain [118,119]. Furthermore, GJ is capable to reduce the homeostasis model assessment ratio (HOMA-R) of diabetic patients [120]. In a streptozotocin-induced diabetic rat model, GJ is found to reduce hyperinsulinemia via the NO pathway [119]. Recently, in a study using rat NAFLD model fed with high-fat diet, GJ treatment significantly reduced the weight of liver and the level of serum AST that elevated by high-fat diet [120]. However, the main effective component (mononer) of GJ for NAFLD therapy needs further investigation.
Rhein (4,5-dihydroxyanthraquinone-2-carboxylic acid) is the major monomer component of Rheum palmatum L., which has been widely used in traditional Chinese medicine for more than 2,000 years. Modern studies pointed out the anti-osteoarthritic properties of rhein in both human and animal models [121,122]. In a highfat diet induced obese and NAFLD mice model, administration of rhein ameliorated NAFLD-associated steatosis, recovered hepatic functions and corrected the T helper (Th)1/Th2 cytokine imbalance. In addition, rhein re-balanced the lipid metabolism through SREBP- 1c and LXR-related pathways [123].
There are numbers of herbal derivatives which exhibit beneficial effects against the development of NAFLD in animal studies, such as sinai san from Chai Hu (Radix Bupleuri) [124], lotus root from Nelumbo nucifera [125], Gynostemma pentaphyllum extract [126], and total alkaloids from Rubus aleaefolius Poir [127]. However, the detailed mechanism for the re-balance of the lipid metabolism by those derivatives is not clear and needs further investigation.
Concluding Remarks
Dysregulation of hepatic lipid metabolism is one of the earliest events during the initiation of NAFLD. It is directly linked to the occurrence of insulin resistance and glucose metabolism impairment, although the exact causal and mechanistic relationship remains poorly understood. Theoretically, the dynamic imbalance between lipogenesis and lipolysis in the liver causes the deposition of lipid in hepatocytes. Therapeutic strategy that retards or reverses the NAFLD progression should at least ameliorate the fat accumulation, through either the reduction of lipogenesis or the enhancement of lipolysis, or both at the same time. Treatment or dietary supplementation with herbal derivatives against NAFLD receives increasing attention recently because these natural compounds have protective properties with minimal adverse effects, when administered in a reasonable dose. The proposed lipid-rebalancing mechanisms of key derivatives in recent studies have been summarized in table 1. However, the lack of long-term clinical evaluation and mechanistic investigation (particularly at the molecular level) hinder the wide application of herbal derivatives in the daily prevention of fatty liver diseases. Future studies should focus on these aspects to further expand the therapeutic application against NAFLD.
	Table 1: Summary of impacts of herbal derivative treatment on hepatic lipid metabolism from recent studies.
References
Bellentani S, Saccoccio G, Masutti F, Crocè LS, Brandi G, et al. (2000) Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med 132: 112-117. Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, et al. (2005) Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288: E462-468. Farrell GC, Wong VW, Chitturi S (2013) NAFLD in Asia--as common and important as in the West. Nat Rev Gastroenterol Hepatol 10: 307-318. Scaglioni F, Ciccia S, Marino M, Bedogni G, Bellentani S (2011) ASH and NASH. Dig Dis 29: 202-210. Korenblat KM, Fabbrini E, Mohammed BS, Klein S (2008) Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology 134: 1369-1375. Gatselis NK, Ntaios G, Makaritsis K, Dalekos GN (2013) Adiponectin: a key playmaker adipocytokine in non-alcoholic fatty liver disease. Clin Exp Med . Domanski JP, Park SJ, Harrison SA (2012) Cardiovascular disease and nonalcoholic fatty liver disease: does histologic severity matter? J Clin Gastroenterol 46: 427-430. Bhala N, Angulo P, van der Poorten D, Lee E, Hui JM, et al. (2011) The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study. Hepatology 54: 1208-1216. Polyzos SA, Kountouras J, Zavos C, Deretzi G (2012) Nonalcoholic fatty liver disease: multimodal treatment options for a pathogenetically multiple-hit disease. J Clin Gastroenterol 46: 272-284. Liu K, Czaja MJ (2013) Regulation of lipid stores and metabolism by lipophagy. Cell Death Differ 20: 3-11. Ding WX, Yin XM (2012) Mitophagy: mechanisms, pathophysiological roles, and analysis. Biol Chem 393: 547-564. Musso G, Gambino R, Cassader M (2009) Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res 48: 1-26. Tarantino G, Scopacasa F, Colao A, Capone D, Tarantino M, et al. (2011) Serum Bcl-2 concentrations in overweight-obese subjects with nonalcoholic fatty liver disease. World J Gastroenterol 17: 5280-5288. Tarantino G, Colao A, Capone D, Conca P, Tarantino M, et al. (2011) Circulating levels of cytochrome C, gamma-glutamyl transferase, triglycerides and unconjugated bilirubin in overweight/obese patients with non-alcoholic fatty liver disease. J Biol Regul Homeost Agents 25: 47-56. Tarantino G, Savastano S, Colao A (2010) Hepatic steatosis, low-grade chronic inflammation and hormone/growth factor/adipokine imbalance. World J Gastroenterol 16: 4773-4783. Tarantino G, Finelli C (2013) What about non-alcoholic fatty liver disease as a new criterion to define metabolic syndrome? World J Gastroenterol 19: 3375-3384. Tarantino G, Lobello R, Scopacasa F, Contaldo F, Pasanisi F, et al. (2007) The contribution of omental adipose tissue to adipokine concentrations in patients with the metabolic syndrome. Clin Invest Med 30: E192-199. Tarantino G, Scalera A, Finelli C (2013) Liver-spleen axis: intersection between immunity, infections and metabolism. World J Gastroenterol 19: 3534-3542. Tarantino G, Conca P, Pasanisi F, Ariello M, Mastrolia M, et al. (2009) Could inflammatory markers help diagnose nonalcoholic steatohepatitis? Eur J Gastroenterol Hepatol 21: 504-511. Xiao J, Guo R, Fung ML, Liong EC, Tipoe GL (2013) Therapeutic approaches to non-alcoholic fatty liver disease: past achievements and future challenges. Hepatobiliary Pancreat Dis Int 12: 125-135. Firenzuoli F, Gori L (2007) Herbal medicine today: clinical and research issues. Evid Based Complement Alternat Med 4: 37-40. Fromenty B, Robin MA, Igoudjil A, Mansouri A, Pessayre D (2004) The ins and outs of mitochondrial dysfunction in NASH. Diabetes Metab 30: 121-138. Begriche K, Igoudjil A, Pessayre D, Fromenty B (2006) Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion 6: 1-28. Reddy JK, Hashimoto T (2001) Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. Annu Rev Nutr 21: 193-230. Sanders RJ, Ofman R, Duran M, Kemp S, Wanders RJ (2006) Omega-oxidation of very long-chain fatty acids in human liver microsomes. Implications for X-linked adrenoleukodystrophy. J Biol Chem 281: 13180-13187. Orrenius S, Gogvadze V, Zhivotovsky B (2007) Mitochondrial oxidative stress: implications for cell death. Annu Rev Pharmacol Toxicol 47: 143-183. Kerner J, Hoppel C (2000) Fatty acid import into mitochondria. Biochim Biophys Acta 1486: 1-17. Nguyen P, Leray V, Diez M, Serisier S, Le Bloc'h J, et al. (2008) Liver lipid metabolism. J Anim Physiol Anim Nutr (Berl) 92: 272-283. Bonnefont JP, Demaugre F, Prip-Buus C, Saudubray JM, Brivet M, et al. (1999) Carnitine palmitoyltransferase deficiencies. Mol Genet Metab 68: 424-440. Yeon JE, Choi KM, Baik SH, Kim KO, Lim HJ, et al. (2004) Reduced expression of peroxisome proliferator-activated receptor-alpha may have an important role in the development of non-alcoholic fatty liver disease. J Gastroenterol Hepatol 19: 799-804. Fan CY, Pan J, Usuda N, Yeldandi AV, Rao MS, et al. (1998) Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-CoA oxidase. Implications for peroxisome proliferator-activated receptor alpha natural ligand metabolism. J Biol Chem 273: 15639-15645 Wanders RJ, Komen J, Kemp S (2011) Fatty acid omega-oxidation as a rescue pathway for fatty acid oxidation disorders in humans. FEBS J 278: 182-194. White DA, Bennett AJ, Billett MA, Salter AM (1998) The assembly of triacylglycerol-rich lipoproteins: an essential role for the microsomal triacylglycerol transfer protein. Br J Nutr 80: 219-229. Liao W, Hui TY, Young SG, Davis RA (2003) Blocking microsomal triglyceride transfer protein interferes with apoB secretion without causing retention or stress in the ER. J Lipid Res 44: 978-985. Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, et al. (2008) Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 134: 424-431. Tarugi P, Averna M (2011) Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum. Adv Clin Chem 54: 81-107. Namikawa C, Shu-Ping Z, Vyselaar JR, Nozaki Y, Nemoto Y, et al. (2004) Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis. J Hepatol 40: 781-786. Gambino R, Cassader M, Pagano G, Durazzo M, Musso G (2007) Polymorphism in microsomal triglyceride transfer protein: a link between liver disease and atherogenic postprandial lipid profile in NASH? Hepatology 45: 1097-1107. Yamazaki T, Sasaki E, Kakinuma C, Yano T, Miura S, et al. (2005) Increased very low density lipoprotein secretion and gonadal fat mass in mice overexpressing liver DGAT1. J Biol Chem 280: 21506-21514. Chen HC, Smith SJ, Ladha Z, Jensen DR, Ferreira LD, et al. (2002) Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1. J Clin Invest 109: 1049-1055. Coleman RA, Lewin TM, Van Horn CG, Gonzalez-Baró MR (2002) Do long-chain acyl-CoA synthetases regulate fatty acid entry into synthetic versus degradative pathways? J Nutr 132: 2123-2126. Pohl J, Ring A, Ehehalt R, Herrmann T, Stremmel W (2004) New concepts of cellular fatty acid uptake: role of fatty acid transport proteins and of caveolae. Proc Nutr Soc 63: 259-262. Razani B, Combs TP, Wang XB, Frank PG, Park DS, et al. (2002) Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities. J Biol Chem 277: 8635-8647. Fernández MA, Albor C, Ingelmo-Torres M, Nixon SJ, Ferguson C, et al. (2006) Caveolin-1 is essential for liver regeneration. Science 313: 1628-1632. Otsu K, Toya Y, Oshikawa J, Kurotani R, Yazawa T, et al. (2010) Caveolin gene transfer improves glucose metabolism in diabetic mice. Am J Physiol Cell Physiol 298: C450-456. Diraison F, Yankah V, Letexier D, Dusserre E, Jones P, et al. (2003) Differences in the regulation of adipose tissue and liver lipogenesis by carbohydrates in humans. J Lipid Res 44: 846-853. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, et al. (2005) Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 115: 1343-1351. Fleischmann M, Iynedjian PB (2000) Regulation of sterol regulatory-element binding protein 1 gene expression in liver: role of insulin and protein kinase B/cAkt. Biochem J 349: 13-17. Azzout-Marniche D, Bécard D, Guichard C, Foretz M, Ferré P, et al. (2000) Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes. Biochem J 350 Pt 2: 389-393. Sewter C, Berger D, Considine RV, Medina G, Rochford J, et al. (2002) Human obesity and type 2 diabetes are associated with alterations in SREBP1 isoform expression that are reproduced ex vivo by tumor necrosis factor-alpha. Diabetes 51: 1035-1041. Foretz M, Pacot C, Dugail I, Lemarchand P, Guichard C, et al. (1999) ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose. Mol Cell Biol 19: 3760-3768. Tomita K, Tamiya G, Ando S, Kitamura N, Koizumi H, et al. (2005) AICAR, an AMPK activator, has protective effects on alcohol-induced fatty liver in rats. Alcohol Clin Exp Res 29: 240S-5S. Deng X, Zhang W, O-Sullivan I, Williams JB, Dong Q, et al. (2012) FoxO1 inhibits sterol regulatory element-binding protein-1c (SREBP-1c) gene expression via transcription factors Sp1 and SREBP-1c. J Biol Chem 287: 20132-20143. Liang G, Yang J, Horton JD, Hammer RE, Goldstein JL, et al. (2002) Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c. J Biol Chem 277: 9520-9528. Dentin R, Pégorier JP, Benhamed F, Foufelle F, Ferré P, et al. (2004) Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP-1c on glycolytic and lipogenic gene expression. J Biol Chem 279: 20314-20326. Ishii S, Iizuka K, Miller BC, Uyeda K (2004) Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription. Proc Natl Acad Sci U S A 101: 15597-15602. Cha JY, Repa JJ (2007) The liver X receptor (LXR) and hepatic lipogenesis. The carbohydrate-response element-binding protein is a target gene of LXR. J Biol Chem 282: 743-751. Dentin R, Benhamed F, Hainault I, Fauveau V, Foufelle F, et al. (2006) Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice. Diabetes 55: 2159-2170. Lefebvre P, Chinetti G, Fruchart JC, Staels B (2006) Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest 116: 571-580. Harano Y, Yasui K, Toyama T, Nakajima T, Mitsuyoshi H, et al. (2006) Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, reduces hepatic steatosis and lipid peroxidation in fatty liver Shionogi mice with hereditary fatty liver. Liver Int 26: 613-620 Ip E, Farrell G, Hall P, Robertson G, Leclercq I (2004) Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice. Hepatology 39: 1286-1296. Tobin JF, Freedman LP (2006) Nuclear receptors as drug targets in metabolic diseases: new approaches to therapy. Trends Endocrinol Metab 17: 284-290. Matsusue K, Haluzik M, Lambert G, Yim SH, Gavrilova O, et al. (2003) Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Invest 111: 737-747. Yang WS, Jeng CY, Wu TJ, Tanaka S, Funahashi T, et al. (2002) Synthetic peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care 25: 376-380 Sun X, Han R, Wang Z, Chen Y (2006) Regulation of adiponectin receptors in hepatocytes by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Diabetologia 49: 1303-1310. Munday MR (2002) Regulation of mammalian acetyl-CoA carboxylase. Biochem Soc Trans 30: 1059-1064. Abu-Elheiga L, Matzuk MM, Abo-Hashema KA, Wakil SJ (2001) Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291: 2613-2616. Savage DB, Choi CS, Samuel VT, Liu ZX, Zhang D, et al. (2006) Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. J Clin Invest 116: 817-824. Harwood HJ Jr (2005) Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition. Expert Opin Ther Targets 9: 267-281. Cohen P, Miyazaki M, Socci ND, Hagge-Greenberg A, Liedtke W, et al. (2002) Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science 297: 240-243. Ntambi JM, Miyazaki M, Stoehr JP, Lan H, Kendziorski CM, et al. (2002) Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc Natl Acad Sci U S A 99: 11482-11486. Dobrzyn P, Dobrzyn A, Miyazaki M, Cohen P, Asilmaz E, et al. (2004) Stearoyl-CoA desaturase 1 deficiency increases fatty acid oxidation by activating AMP-activated protein kinase in liver. Proc Natl Acad Sci U S A 101: 6409-6414. Miyazaki M, Flowers MT, Sampath H, Chu K, Otzelberger C, et al. (2007) Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and hepatic steatosis. Cell Metab 6: 484-496. Liu X, Strable MS, Ntambi JM (2011) Stearoyl CoA desaturase 1: role in cellular inflammation and stress. Adv Nutr 2: 15-22. Mason P, Liang B, Li L, Fremgen T, Murphy E, et al. (2012) SCD1 inhibition causes cancer cell death by depleting mono-unsaturated fatty acids. PLoS One 7: e33823. Wiegman CH, Bandsma RH, Ouwens M, van der Sluijs FH, Havinga R, et al. (2003) Hepatic VLDL production in ob/ob mice is not stimulated by massive de novo lipogenesis but is less sensitive to the suppressive effects of insulin. Diabetes 52: 1081-1089. Chakravarthy MV, Pan Z, Zhu Y, Tordjman K, Schneider JG, et al. (2005) "New" hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab 1: 309-322. Amagase H, Farnsworth N (2011) A review of botanical characteristics, phytochemistry, clinical relevance in efficacy and safety of Lycium barbarum fruit (Goji). Food Res Int 44: 1702-1717 Chang RC, So KF (2008) Use of anti-aging herbal medicine, Lycium barbarum, against aging-associated diseases. What do we know so far? Cell Mol Neurobiol 28: 643-652. Cheng D, Kong H (2011) The effect of Lycium barbarum polysaccharide on alcohol-induced oxidative stress in rats. Molecules 16: 2542-2550. Xiao J, Liong EC, Ching YP, Chang RC, So KF, et al. (2012) Lycium barbarum polysaccharides protect mice liver from carbon tetrachloride-induced oxidative stress and necroinflammation. J Ethnopharmacol 139: 462-470 Xiao J, Ching YP, Liong EC, Nanji AA, Fung ML, et al. (2013) Garlic-derived S-allylmercaptocysteine is a hepato-protective agent in non-alcoholic fatty liver disease in vivo animal model. Eur J Nutr 52: 179-191. Xiao J, Ho CT, Liong EC, Nanji AA, Leung TM, et al. (2013) Epigallocatechin gallate attenuates fibrosis, oxidative stress, and inflammation in non-alcoholic fatty liver disease rat model through TGF/SMAD, PI3 K/Akt/FoxO1, and NF-kappa B pathways. Eur J Nutr . Schadinger SE, Bucher NL, Schreiber BM, Farmer SR (2005) PPARgamma2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes. Am J Physiol Endocrinol Metab 288: E1195-1205. Xiao J, Liong EC, Ching YP, Chang RC, Fung ML, et al. (2013) Lycium barbarum polysaccharides protect rat liver from non-alcoholic steatohepatitis-induced injury. Nutr Diabetes 3: e81. Cardellina JH II (2013) Review of Garlic and Other Alliums. The Lore and the Science Garlic and Other Alliums. The Lore and the Science. J Nat Prod 76: 813 Sumioka I, Matsura T, Kasuga S, Itakura Y, Yamada K (1998) Mechanisms of protection by S-allylmercaptocysteine against acetaminophen-induced liver injury in mice. Jpn J Pharmacol 78: 199-207. Xiao J, Liong EC, Ling MT, Ching YP, Fung ML, et al. (2012) S-allylmercaptocysteine reduces carbon tetrachloride-induced hepatic oxidative stress and necroinflammation via nuclear factor kappa B-dependent pathways in mice. Eur J Nutr 51: 323-333 Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, et al. (2009) Autophagy regulates lipid metabolism. Nature 458: 1131-1135. Mitscher LA, Jung M, Shankel D, Dou JH, Steele L, et al. (1997) Chemoprotection: a review of the potential therapeutic antioxidant properties of green tea (Camellia sinensis) and certain of its constituents. Med Res Rev 17: 327-365. Bruno RS, Dugan CE, Smyth JA, DiNatale DA, Koo SI (2008) Green tea extract protects leptin-deficient, spontaneously obese mice from hepatic steatosis and injury. J Nutr 138: 323-331. Park HJ, DiNatale DA, Chung MY, Park YK, Lee JY, et al. (2011) Green tea extract attenuates hepatic steatosis by decreasing adipose lipogenesis and enhancing hepatic antioxidant defenses in ob/ob mice. J Nutr Biochem 22: 393-400. Kang JS, Lee WK, Yoon WK, Kim N, Park SK, et al. (2011) A combination of grape extract, green tea extract and L-carnitine improves high-fat diet-induced obesity, hyperlipidemia and non-alcoholic fatty liver disease in mice. Phytother Res 25: 1789-1795. Murase T, Nagasawa A, Suzuki J, Hase T, Tokimitsu I (2002) Beneficial effects of tea catechins on diet-induced obesity: stimulation of lipid catabolism in the liver. Int J Obes Relat Metab Disord 26: 1459-1464. Dulloo AG, Duret C, Rohrer D, Girardier L, Mensi N, et al. (1999) Efficacy of a green tea extract rich in catechin polyphenols and caffeine in increasing 24-h energy expenditure and fat oxidation in humans. Am J Clin Nutr 70: 1040-1045. Masterjohn C, Bruno RS (2012) Therapeutic potential of green tea in nonalcoholic fatty liver disease. Nutr Rev 70: 41-56. Singh BN, Shankar S, Srivastava RK (2011) Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. Biochem Pharmacol 82: 1807-1821. Ramprasath VR, Jones PJ (2010) Anti-atherogenic effects of resveratrol. Eur J Clin Nutr 64: 660-668. Jang JH, Surh YJ (2001) Protective effects of resveratrol on hydrogen peroxide-induced apoptosis in rat pheochromocytoma (PC12) cells. Mutat Res 496: 181-190. Floreani M, Napoli E, Quintieri L, Palatini P (2003) Oral administration of trans-resveratrol to guinea pigs increases cardiac DT-diaphorase and catalase activities, and protects isolated atria from menadione toxicity. Life Sci 72: 2741-2750. Leiro J, Alvarez E, Arranz JA, Laguna R, Uriarte E, et al. (2004) Effects of cis-resveratrol on inflammatory murine macrophages: antioxidant activity and down-regulation of inflammatory genes. J Leukoc Biol 75: 1156-1165. Hubbard BP, Gomes AP, Dai H, Li J, Case AW, et al. (2013) Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339: 1216-1219. Zlotogorski A, Dayan A, Dayan D, Chaushu G, Salo T, et al. (2013) Nutraceuticals as new treatment approaches for oral cancer: II. Green tea extracts and resveratrol. Oral Oncol 49: 502-506. Shang J, Chen LL, Xiao FX, Sun H, Ding HC, et al. (2008) Resveratrol improves non-alcoholic fatty liver disease by activating AMP-activated protein kinase. Acta Pharmacol Sin 29: 698-706. Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, et al. (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127: 1109-1122. Wang GL, Fu YC, Xu WC, Feng YQ, Fang SR, et al. (2009) Resveratrol inhibits the expression of SREBP1 in cell model of steatosis via Sirt1-FOXO1 signaling pathway. Biochem Biophys Res Commun 380: 644-649. Gómez-Zorita S, Fernández-Quintela A, Macarulla MT, Aguirre L, Hijona E, et al. (2012) Resveratrol attenuates steatosis in obese Zucker rats by decreasing fatty acid availability and reducing oxidative stress. Br J Nutr 107: 202-210. Xin P, Han H, Gao D, Cui W, Yang X, et al. (2013) Alleviative effects of resveratrol on nonalcoholic fatty liver disease are associated with up regulation of hepatic low density lipoprotein receptor and scavenger receptor class B type I gene expressions in rats. Food Chem Toxicol 52: 12-18. Medical News Today (2008) Sirtris Announces SRT501 Lowers Glucose In Twice-Daily Dosing Clinical Trial Cacciapuoti F, Scognamiglio A, Palumbo R, Forte R, Cacciapuoti F (2013) Silymarin in non alcoholic fatty liver disease. World J Hepatol 5: 109-113. Federico A, Trappoliere M, Tuccillo C, de Sio I, Di Leva A, et al. (2006) A new silybin-vitamin E-phospholipid complex improves insulin resistance and liver damage in patients with non-alcoholic fatty liver disease: preliminary observations. Gut 55: 901-902. Salamone F, Galvano F, Cappello F, Mangiameli A, Barbagallo I, et al. (2012) Silibinin modulates lipid homeostasis and inhibits nuclear factor kappa B activation in experimental nonalcoholic steatohepatitis. Transl Res 159: 477-486. Kuo JJ, Chang HH, Tsai TH, Lee TY (2012) Positive effect of curcumin on inflammation and mitochondrial dysfunction in obese mice with liver steatosis. Int J Mol Med 30: 673-679. Kang Q, Chen A (2009) Curcumin suppresses expression of low-density lipoprotein (LDL) receptor, leading to the inhibition of LDL-induced activation of hepatic stellate cells. Br J Pharmacol 157: 1354-1367. Gutiérrez-Grobe Y, Chávez-Tapia N, Sánchez-Valle V, Gavilanes-Espinar JG, Ponciano-Rodríguez G, et al. (2012) High coffee intake is associated with lower grade nonalcoholic fatty liver disease: the role of peripheral antioxidant activity. Ann Hepatol 11: 350-355 Molloy JW, Calcagno CJ, Williams CD, Jones FJ, Torres DM, et al. (2012) Association of coffee and caffeine consumption with fatty liver disease, nonalcoholic steatohepatitis, and degree of hepatic fibrosis. Hepatology 55: 429-436. Vitaglione P, Morisco F, Mazzone G, Amoruso DC, Ribecco MT, et al. (2010) Coffee reduces liver damage in a rat model of steatohepatitis: the underlying mechanisms and the role of polyphenols and melanoidins. Hepatology 52: 1652-1661. Tawata M, Kurihara A, Nitta K, Iwase E, Gan N, et al. (1994) The effects of goshajinkigan, a herbal medicine, on subjective symptoms and vibratory threshold in patients with diabetic neuropathy. Diabetes Res Clin Pract 26: 121-128. Sakamoto N, Sato Y, Goto Y, Ikeda Y, Takahashi A, et al. (1987) Treatment of diabetic neuropathy with traditional oriental medicine – comparison between gosha-jinki-gan and mecobalamin treatment. J Jpn Diabetic Soc 30: 729-737 Hirotani Y, Doi A, Takahashi T, Umezawa H, Urashima Y, et al. (2012) Protective effects of the herbal medicine goshajinkigan in a rat model of non-alcoholic fatty liver disease. Biomed Res 33: 373-376. Taccoen A, Berdah L (1993) [Diacetylrhein, a new therapeutic approach of osteoarthritis]. Rev Rhum Ed Fr 60: 83S-86S. Brandt KD, Smith G, Kang SY, Myers S, O'Connor B, et al. (1997) Effects of diacerhein in an accelerated canine model of osteoarthritis. Osteoarthritis Cartilage 5: 438-449. Sheng X, Wang M, Lu M, Xi B, Sheng H, et al. (2011) Rhein ameliorates fatty liver disease through negative energy balance, hepatic lipogenic regulation, and immunomodulation in diet-induced obese mice. Am J Physiol Endocrinol Metab 300: E886-E893 Zhang Q, Zhao Y, Zhang DB, Sun LJ (2005) Effect of Sinai san decoction on the development of non-alcoholic steatohepatitis in rats. World J Gastroenterol 11: 1392-1395. Tsuruta Y, Nagao K, Shirouchi B, Nomura S, Tsuge K, et al. (2012) Effects of lotus root (the edible rhizome of Nelumbo nucifera) on the deveolopment of non-alcoholic fatty liver disease in obese diabetic db/db mice. Biosci Biotechnol Biochem 76: 462-466. Müller C, Gardemann A, Keilhoff G, Peter D, Wiswedel I, et al. (2012) Prevention of free fatty acid-induced lipid accumulation, oxidative stress, and cell death in primary hepatocyte cultures by a Gynostemma pentaphyllum extract. Phytomedicine 19: 395-401. Zhao J, Zheng H, Liu Y, Lin J, Zhong X, et al. (2013) Anti-inflammatory effects of total alkaloids from Rubus aleaefolius Poir. on non-alcoholic fatty liver disease through regulation of the NF-ÎºB pathway. Int J Mol Med 31: 931-937. Seo DY, Lee S, Figueroa A, Kwak YS, Kim N, et al. (2012) Aged garlic extract enhances exercise-mediated improvement of metabolic parameters in high fat diet-induced obese rats. Nutr Res Pract 6: 513-519. Lee S, Joo H, Kim CT, Kim IH, Kim Y (2012) High hydrostatic pressure extract of garlic increases the HDL cholesterol level via up-regulation of apolipoprotein A-I gene expression in rats fed a high-fat diet. Lipids Health Dis 11: 77.

Journal of Food and Nutritional DisordersISSN: 2324-9323

Hepatic Lipid Metabolism and Herbal Impacts on Non-Alcoholic Fatty Liver Disease

Abstract

Introduction

Hepatic Lipid Metabolism During NAFLD Pathogenesis

Impacts of Some Herbal Derivatives on Lipid Metabolism During NAFLD

Concluding Remarks

References

Track Your Manuscript

Explore SciTechnol

Google Scholar citation report

Citations : 848

Journal of Food and Nutritional Disorders peer review process verified at publons

Journal Highlights

Tweets by @