Acanthoic acid modulates lipogenesis in nonalcoholic fatty liver disease via FXR/LXRs-dependent manner

OBJECTIVE To reveal the effect and mechanism of acanthoic acid(AA) on nonalcoholic fatty liver disease(NAFLD) associated with lipid accumulation by activating Farnesoid X receptor(FXR) and liver X receptors(LXRs) signaling. METHODS C57 BL/6 mice were received a modified Lieber-De Carli diet with 71%high-fat(L-D) and treated with AA(20 and 40 mg·kg~(-1)) or equal volume of saline for 12 weeks. The regulation of AA on lipid accumulation was also detected in pro-steatotic stimulated AML12 cells with palmitic acid(PA).RESULTS When L-D diet-fed mice were treated with AA, loss in body mass, liver index, and liver lipid droplet were observed along with reduced triglyceride(TG) and serum transaminase. Furthermore, AA decreased sterol regulatory element binding protein 1(SREBP-1) and target genes expression, regulated PPARα and PPARγ expressions, ameliorated hepatic fibrosis markers, enhanced hepatic FXR and LXR, and regulated AMPK-LKB1 and SIRT1 signaling pathway. Moreover, AA attenuated lipid accumulation via FXR and LXR activation in steatotic AML-12 cells, which was confirmed by guggulsterones(FXR antagonist) or GW3965(LXR agonist). CONCLUSION Activation of FXR and LXR signaling caused by AA might increase AMPK-SIRT1 signaling and then contribute to modulating lipid accumulation and fatty acid synthesis, which suggested that activated FXR-LXR axis by AA represented an effective strategy for relieving NAFLD.     

Ochratoxin A Induces Steatosis via PPARγ-CD36 Axis

Ochratoxin A(OTA) is considered to be one of the most important contaminants of food and feed worldwide. The liver is one of key target organs for OTA to exert its toxic effects. Due to current lifestyle and diet, nonalcoholic fatty liver disease (NAFLD) has been the most common liver disease. To examine the potential effect of OTA on hepatic lipid metabolism and NAFLD, C57BL/6 male mice received 1 mg/kg OTA by gavage daily. Compared with controls, OTA increased lipid deposition and TG accumulation in mouse livers. In vitro OTA treatment also promoted lipid droplets accumulation in primary hepatocytes and HepG2 cells. Mechanistically, OTA prevented PPARγ degradation by reducing the interaction between PPARγ and its E3 ligase SIAH2, which led to activation of PPARγ signaling pathway. Furthermore, downregulation or inhibition of CD36, a known of PPARγ, alleviated OTA-induced lipid droplets deposition and TG accumulation. Therefore, OTA induces hepatic steatosis via PPARγ-CD36 axis, suggesting that OTA has an impact on liver lipid metabolism and may contribute to the development of metabolic diseases.     

The herbal composition GGEx18 from Laminaria japonica, Rheum palmatum, and Ephedra sinica inhibits high-fat diet-induced hepatic steatosis via hepatic PPARα activation

Context: The activation of peroxisome proliferator-activated receptor α (PPARα) target genes promotes hepatic oxidation of fatty acids. We hypothesized that Gyeongshingangjeehwan 18 (GGEx18), a mixture of three herbs, Laminaria japonica Aresch (Laminariaceae), Rheum palmatum L. (Polygonaceae), and Ephedra sinica Stapf (Ephedraceae), can regulate high-fat diet-induced hepatic steatosis through PPARα activation in the liver. Objective: To investigate the effects of GGEx18 on obesity-related hepatic steatosis and the responsible mechanism. Materials and methods: The effects of GGEx18 on hepatic lipid accumulation, serum lipid profiles, and the expression of PPARα target genes were studied in high-fat diet-induced obese mice. The effects of GGEx18 on the expression of the PPARα targets and PPARα reporter gene activation were measured in NMu2Li liver cells. Results: GGEx18 administration to obese mice for 9 weeks markedly (p?相似文献   

Rutin exhibits hepatoprotective effects in a mouse model of non-alcoholic fatty liver disease by reducing hepatic lipid levels and mitigating lipid-induced oxidative injuries

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic lipids and oxidative injury of hepatocytes. Rutin is a natural flavonoid with significant roles in combating cellular oxidative stress and regulating lipid metabolism. The current study aims to investigate the molecular mechanisms underlying rutin's hypolipidemic and hepatoprotective effects in nonalcoholic fatty liver disease. Rutin treatment was applied to male C57BL/6 mice maintained on a high-fat diet and HepG2 cells challenged with oleic acid. Hepatic lipid accumulation was evaluated by triglyceride assay and Oil Red O staining. Oxidative hepatic injury was assessed by malondialdehyde assay, superoxide dismutase assay and reactive oxygen species assay. The expression levels of various lipogenic and lipolytic genes were determined by quantitative real-time polymerase chain reactions. In addition, liver autophagy was investigated by enzyme-linked immunosorbent assay. In both fat-challenged murine liver tissues and HepG2 cells, rutin treatment was shown to significantly lower triglyceride content and the abundance of lipid droplets. Rutin was also found to reduce cellular malondialdehyde level and restore superoxide dismutase activity in hepatocytes. Among the various lipid-related genes, rutin treatment was able to restore the expression of peroxisome proliferator-activated receptor alpha (PPAR-α) and its downstream targets, carnitine palmitoyltransferase 1 and 2 (CPT-1 and CPT-2), while suppressing those of sterol regulatory element-binding protein 1c (SREBP-1c), diglyceride acyltransfase 1 and 2 (DGAT-1 and 2), as well as acyl-CoA carboxylase (ACC). In addition, rutin was shown to repress the autophagic function of liver tissues by down-regulating key autophagy biomarkers, including tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β). The experimental data demonstrated that rutin could reduce triglyceride content and mitigate oxidative injuries in fat-enriched hepatocytes. The hypolipidemic properties of rutin could be attributed to its ability to simultaneously facilitate fatty acid metabolism and inhibit lipogenesis.     

Therapeutic potential of traditional Chinese medicine for the treatment of NAFLD: A promising drug Potentilla discolor Bunge

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic lipids and metabolic stress-induced liver injury. There are currently no approved effective pharmacological treatments for NAFLD. Traditional Chinese medicine (TCM) has been used for centuries to treat patients with chronic liver diseases without clear disease types and mechanisms. More recently, TCM has been shown to have unique advantages in the treatment of NAFLD. We performed a systematic review of the medical literature published over the last two decades and found that many TCM formulas have been reported to be beneficial for the treatment of metabolic dysfunctions, including Potentilla discolor Bunge (PDB). PDB has a variety of active compounds, including flavonoids, terpenoids, organic acids, steroids and tannins. Many compounds have been shown to exhibit a series of beneficial effects for the treatment of NAFLD, including anti-oxidative and anti-inflammatory functions, improvement of lipid metabolism and reversal of insulin resistance. In this review, we summarize potential therapeutic effects of TCM formulas for the treatment of NAFLD, focusing on the medicinal properties of natural active compounds from PDB and their underlying mechanisms. We point out that PDB can be classified as a novel candidate for the treatment and prevention of NAFLD.     

红雪茶提取物降脂保肝作用的实验研究

目的研究红雪茶提取物(HXC)对大鼠非酒精性脂肪肝(NAFLD)的降脂保肝作用。方法采用高糖高脂饲料建立NAFLD大鼠模型,同时分别采用不同剂量的HXC(含生药0.9、2.7g.kg-1.d-1)以及复方蛋氨酸胆碱片(1.2g.kg-1.d-1)进行防治。实验6周后,观察大鼠肝脏病理变化并检测各组血清丙氨酸氨基转移酶(ALT)、天门冬酸氨基转移酶(AST)、三酰甘油(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)和肝组织TC、TG、丙二醛(MDA)、超氧化物歧化酶(SOD)的水平。结果与模型组相比,HXC高剂量可以明显降低肝湿质量与肝指数,显著降低血清中的ALT、AST、TC、TG、LDL-C及肝组织中的TC、TG、MDA,升高血清中的HDL-C及肝组织中的SOD,脂肪变性和水样变性程度明显减轻。结论 HXC对高糖高脂饮食诱发的大鼠NAFLD具有明显的改善作用,其机制可能与调节血脂、减少脂质在肝脏中堆积以及提高机体抗氧化活力,抑制脂质过氧化反应有关。     

Screening for the efficacy on lipid accumulation in 3T3-L1 cells is an effective tool for the identification of new anti-diabetic compounds

Reducing lipid accumulation in insulin target tissues is critical for the treatment of type 2 diabetes. This study aimed to develop a biochemical assay in cells for high throughput (HTP) screening of anti-diabetic drugs by reducing lipid accumulation via different mechanisms. We designed a new method to extract triglyceride (TG) with KOH to allow biochemical quantification of TGs for HTP screening in 3T3-L1 cells. This new method was validated for its biochemical properties with identical results of TG obtained with or without KOH (r(2)=0.9978, p<0.001) and a fourfold improvement in TG extraction recovery rate (88-95%, p<0.001) as compared to the conventional chloroform/methanol extraction (12-18%). The ability of this phenotype screening to capture potential anti-diabetic drugs was verified by pharmacological agents well known to alter lipid accumulation by different mechanisms including AMPK activators, fatty acid synthesis inhibitors, PPARγ activator and several lipogenic substrates. To further demonstrate the application of this screening tool for discovery of new anti-diabetic drugs, we screened >200 new candidates selected from Chinese medicine and identified 49 compounds from different classes which reduced TG content by >50% at 1μM or >75% at 10μM. Finally, we tested two selected leads (albiflorin and oxymatrine) in vivo and confirmed their efficacy in reducing visceral adiposity, glucose intolerance and hepatic steatosis in high fat-fed or high fructose-fed mice. Our results indicate that screening for the efficacy on lipid accumulation in cells by biochemical quantification of TGs with KOH extraction is an effective tool for the identification of new anti-diabetic compounds.     

水林佳治疗非酒精性脂肪肝的疗效观察

目的:探讨水林佳治疗非酒精性脂肪肝的疗效。方法:随机选择非酒精性脂肪肝患者90例,试验组46例,服用水林佳105mg,3次/日;对照组44例,口服硫普罗宁100 mg,3次/日,观察期为3个月。治疗前后检测肝转氨酶、血胆固醇、甘油三酯、肝纤维谱及超声影像变化。同时观察两组患者用药期间的不良反应。结果:治疗结束时,试验组ALT、AST、TC、TG及HA、LN、PC-Ⅲ均明显下降,肝脏影像学也有明显改善。对照组虽ALT、AST有所下降,但HA、LN、PC-Ⅲ和肝脏影像学无明显改善。观察期间两组均未出现明显不良反应。结论:水林佳具有保肝、降血脂、改善肝纤维化的作用,对非酒精性脂肪肝有治疗作用。     

PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells

Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various PPAR agonists, i.e. fenofibrate, bezafibrate, troglitazone, rosiglitazone, muraglitazar and tesaglitazar on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stained by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists. The greatest effects on reduction of steatosis were obtained with the dual PPARα/γ agonist muraglitazar. Such improvement of steatosis was associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of many genes involved in lipogenesis. Moreover, modulation of expression of some nuclear receptor genes, such as FXR, LXRα and CAR, which are potent actors in the control of lipogenesis, was observed and might explain repression of de novo lipogenesis.     

非酒精性脂肪性肝病发病机制的研究进展

非酒精性脂肪性肝病（NAFLD）是指与过量饮酒无关的临床综合征,主要病理改变包括肝细胞弥漫性脂肪变性和脂肪堆积。NAFLD动物模型表现出显著的肝脏微循环障碍,关于其形成机制,被广为接受的为＂二次打击＂学说。该学说认为肥胖、胰岛素抵抗等因素作为＂第一次打击＂,导致肝脏中脂质堆积,形成单纯性脂肪肝,增加了＂第二次打击＂造成的肝脏损伤的易感性,这些因素包括炎症、枯否细胞功能障碍、氧化应激、线粒体障碍、脂肪因子调节紊乱等,导致非酒精性脂肪性肝炎甚至纤维化等更严重疾病的发生。     

Salacia oblonga root improves postprandial hyperlipidemia and hepatic steatosis in Zucker diabetic fatty rats: activation of PPAR-alpha

Salacia oblonga (SO) root is an Ayurvedic medicine with anti-diabetic and anti-obese properties. Peroxisome proliferator-activated receptor (PPAR)-alpha, a nuclear receptor, plays an important role in maintaining the homeostasis of lipid metabolism. Here, we demonstrate that chronic oral administration of the water extract from the root of SO to Zucker diabetic fatty (ZDF) rats, a genetic model of type 2 diabetes and obesity, lowered plasma triglyceride and total cholesterol (TC) levels, increased plasma high-density lipoprotein levels and reduced the liver contents of triglyceride, non-esterified fatty acids (NEFA) and the ratio of fatty droplets to total tissue. By contrast, the extract had no effect on plasma triglyceride and TC levels in fasted ZDF rats. After olive oil administration to ZDF the extract also inhibited the increase in plasma triglyceride levels. These results suggest that SO extract improves postprandial hyperlipidemia and hepatic steatosis in ZDF rats. Additionally, SO treatment enhanced hepatic expression of PPAR-alpha mRNA and protein, and carnitine palmitoyltransferase-1 and acyl-CoA oxidase mRNAs in ZDF rats. In vitro, SO extract and its main component mangiferin activated PPAR-alpha luciferase activity in human embryonic kidney 293 cells and lipoprotein lipase mRNA expression and enzyme activity in THP-1 differentiated macrophages; these effects were completely suppressed by a selective PPAR-alpha antagonist MK-886. The findings from both in vivo and in vitro suggest that SO extract functions as a PPAR-alpha activator, providing a potential mechanism for improvement of postprandial hyperlipidemia and hepatic steatosis in diabetes and obesity.     

The herbal composition GGEx18 from Laminaria japonica,Rheum palmatum,and Ephedra sinica inhibits high-fat diet-induced hepatic steatosis via hepatic PPARα activation

Context: The activation of peroxisome proliferator-activated receptor α (PPARα) target genes promotes hepatic oxidation of fatty acids. We hypothesized that Gyeongshingangjeehwan 18 (GGEx18), a mixture of three herbs, Laminaria japonica Aresch (Laminariaceae), Rheum palmatum L. (Polygonaceae), and Ephedra sinica Stapf (Ephedraceae), can regulate high-fat diet-induced hepatic steatosis through PPARα activation in the liver.

Objective: To investigate the effects of GGEx18 on obesity-related hepatic steatosis and the responsible mechanism.

Materials and methods: The effects of GGEx18 on hepatic lipid accumulation, serum lipid profiles, and the expression of PPARα target genes were studied in high-fat diet-induced obese mice. The effects of GGEx18 on the expression of the PPARα targets and PPARα reporter gene activation were measured in NMu2Li liver cells.

Results: GGEx18 administration to obese mice for 9 weeks markedly (p?<?0.05) decreased hepatic lipid accumulation compared with that in obese control mice. Serum triglyceride and total cholesterol levels were significantly (p <0.05) decreased by GGEx18. GGEx18 treatment increased the messenger RNA levels of PPARα target genes, which are responsible for fatty acid oxidation, in liver tissues. Consistent with the in vivo data, similar activation of genes was observed in GGEx18-treated NMu2Li liver cells. GGEx18 also elevated PPARα reporter gene expression in NMu2Li cells.

Discussion and conclusion: These results suggest that GGEx18 prevents hepatic steatosis and hyperlipidemia in high-fat diet-induced obese mice, and this process may be mediated through PPARα activation in the liver.     

Are statins ‘IDEAL’ for non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and cause of elevated serum liver enzyme activities in the developed world1. Obesity, diabetes mellitus (DM), and dyslipidaemia, common components of the metabolic syndrome (MetS), are frequently associated with NAFLD; 75–100% of patients with MetS or DM have NAFLD2. NAFLD is characterized by hepatic triglyceride (TG) infiltration in the absence of alcohol abuse or chronic liver disease1. NAFLD includes a spectrum of conditions varying from steatosis to steatosis with inflammation [steatohepatitis (NASH)], necrosis, fibrosis or cirrhosis that rarely progresses to hepatocellular carcinoma3. NAFLD and NASH are the hepatic manifestations of MetS and are associated with increased cardiovascular disease (CVD) risk4. Most NAFLD/NASH patients die from CVD rather than from liver disease4,5. There is no universally accepted treatment for NAFLD1-5.     

酒精性脂肪肝脂质代谢研究进展

酒精性脂肪肝(AFL)是长期大量饮用酒精引发的肝脏损害性病变,可逆转也可进一步发展为肝纤维化和肝硬化。众多的脂肪细胞因子如瘦素(Leptin)、抵抗素(Resistin)和肿瘤坏死因子-α(TNF-α)在脂肪肝的发病中起到一定的促进作用,脂联素(Adiponectin)能改善脂质代谢,延缓脂肪肝的发生;脂联素通过腺苷酸活化蛋白激酶(AMPK)调节糖脂代谢、改善胰岛素敏感性。脂联素/AMPK信号通路是酒精在肝脏的作用靶点、也是调节PPARγ作用的重要信号通路;脂肪分化相关蛋白(ADRP)调节脂质代谢、促进酒精性脂肪肝的形成;过氧化物酶增殖体激活受体γ(PPARγ)参与机体脂质稳态的调节,脂肪肝时PPARγ表达增高,肝纤维化时PPARγ表达减少。对酒精性脂肪肝脂质代谢的深入研究,有助于阐明酒精性脂肪肝发病机制并为临床防治ALD及脂质代谢相关疾病提供新策略。     

PPAR激动剂在治疗非酒精性脂肪性肝病中的应用前景

由于肥胖症和2型糖尿病患者越来越多,非酒精性脂肪性肝病(NAFLD)也呈现逐年上升趋势。NAFLD可引起肝硬化和肝癌等并发症,严重威胁公众健康,目前尚无有效治疗NAFLD及其并发症的药物。肝脏甘油三酯聚集是NAFLD的重要标志,过氧化物酶体增殖物活化受体(PPAR)可参与脂代谢、糖代谢以及炎症的调控。本文综述了PPAR参与NAFLD的可能作用机制以及治疗NAFLD的PPAR激动剂的研究进展。     

Regulation effects of rosemary(Rosmarinus officinalis Linn) on hepatic lipid metabolism in OA induced NAFLD rats

OBJECTIVE To highlight the pharmacological effects of rosemary and its active compounds and elucidate its related mechanisms in nonalcoholic fatty liver disease(NAFLD) management both in vitro and in vivo. METHODS In orotic acid induced NAFLD rats model, rats were administrated with 100, 200 and 400 mg·kg~(-1) rosemary ethanol extract(RO), 10, 25 and 50 mg·kg~(-1) rosemary acid(RA), and 5, 10 and 25 mg·kg~(-1) carnosic acid(CA) for three weeks respec-tively. Sodium oleate induced HepG2 cell model was used to study the regulation effect of rosemary ethanol extract and its main metabolites on fat accumulation. lipid metabolism related gene expression was analyzed by Western blotting and real-time PCR to clarify the specific molecular mechanism of RO, RA and CA in lipid accumulation. RESULTS RO,RA and CA significantly reduced the contents of liver triglyceride(TG), total cholesterol(TC), free fatty acids(FFA) and improved cell hypertrophy, vacuolation, and cell necrosis in liver of orotic acid induced NAFLD model rats. The mechanism and related pathways of RO and its main metabolites against lipid disorder was related to the up-regulation of the phosphorylation of adenosine 5′-monophosphate(AMP)-activated protein kinase(AMPK) and inhibition of the sterol regulatory element binding protein-1 c(SREBP-1 c) cracking into the nuclear, following down-regulation of fatty acid synthesis.CONCLUSION The rosemary has effectively function to regulate lipid metabolism through AMPK/SREBP1 c signaling pathway.     

Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis

Non-alcoholic fatty liver disease (NAFLD) is characterized by the aberrant accumulation of triglycerides in hepatocytes in the absence of significant alcohol consumption, viral infection or other specific causes of liver disease. NAFLD has become a burgeoning health problem both worldwide and in China, but its pathogenesis remains poorly understood. Farnesoid X receptor (FXR), a member of the nuclear receptor (NR) superfamily, has been demonstrated to be the primary sensor for endogenous bile acids, and play a crucial role in hepatic triglyceride homeostasis. Deciphering the synergistic contributions of FXR to triglyceride metabolism is critical for discovering therapeutic agents in the treatment of NAFLD and hypertriglyceridemia.     

壳聚糖合并中药对实验性大鼠脂肪肝的治疗作用

目的；研究壳聚糖合并中药对脂肪肝的治疗作用。方法：采用小剂量四氯化碳合并高脂饮食建立大鼠脂肪肝模型。给予壳聚糖合并中药治疗，以肝脏的脂质含量及组织形态学变化为衡量标准。观察其治疗效果。结果：四氯化碳合并高脂饮食可引起大鼠肝脏明显的脂肪变性，表现为肝组织甘油三酯（TG），总胆固醇（TC），游离脂肪酸（FFA）含量显著增加，病理检查显示；肝细胞肿胀，内部充满大小不等的脂滴；壳聚糖加中药治疗组大鼠肝脏TG，TC，FFA含量显著降低。肝细胞脂变程度明显减轻。结论：壳聚糖合并中药可明显降低肝脂肪含量，对脂肪肝有明显的治疗作用。