肝细胞L-FABP、FATP4在大鼠非酒精性脂肪性肝病形成中的表达及意义

目的研究肝脏型脂肪酸结合蛋白（L—FABP）、4型脂肪酸转运蛋白（FATP4）在大鼠非酒精性脂肪性肝病（NAFLD）发病机制中的表达及意义。方法建立高脂饮食脂肪肝模型，用定量逆转录聚合酶链反应与半定量聚丙烯凝胶蛋白电泳方法测定脂肪肝肝组织中L—FABP、FATP4表达变化。结果高脂饮食脂肪肝大鼠肝脏中L—FABP于2周时其mRNA及蛋白表达增强，12周时表达最为明显，与正常组比较，差异有统计学意义；FATP4 mRNA水平及蛋白表达趋势同L—FABP，结果基本相近似（L—FABP mRNA，F=124．9；蛋白表达，F=92．6；FATP4 mRNA，F=602．9；蛋白表达，F=108．8，JD值均〈0．05）。结论高脂饮食引起L—FABP、FATP4表达增强，最初是一种适应性反应，随着L—FABP、FATP4表达进一步增强，导致脂肪酸代谢失衡，引起脂肪肝的发生。     

卡维地洛减弱肥厚心肌能量代谢向胚胎型转换的分子机制

目的 :观察压力负荷性大鼠肥厚心肌能量代谢的转换模式及卡维地洛的作用 ,探讨卡维地洛减弱压力负荷性心肌能量代谢胚胎型转换的分子调控机制。方法 :用卡维地洛治疗腹主动脉缩窄术后 4周的雄性 Waster大鼠 ,治疗 12周后观察假手术组、腹主动脉缩窄组和卡维地洛干预组大鼠血流动力学参数、心室重构指标、血清和心肌游离脂肪酸的含量及肌型肉毒碱棕榈酰转移酶 I（ M-CPT-I）和中链脂酰辅酶 A脱氢酶 （ MCAD） m RNA的表达变化。结果 :术后 16周大鼠左室心肌明显肥厚 ,血清和心肌游离脂肪酸的含量增加 ,左室肥厚心肌 M-CPT-I和MCAD m RNA的表达下调。卡维地洛治疗 12周后能够明显改善上述变化。结论 :压力负荷性大鼠肥厚心肌能量代谢模式发生胚胎型转换 ;卡维地洛能够减少左室心肌脂肪酸氧化限速酶和关键酶的基因表达 ,减弱心肌胚胎型能量代谢的转换     

Peroxisome proliferator-activated receptors: finding the orphan a home

The peroxisome proliferator-activated receptor (PPAR) is a member of the steroid hormone receptor superfamily and is activated by a variety of fibrate hypolipidaemic drugs and non-genotoxic rodent hepatocarcinogens that are collectively termed peroxisome proliferators. A key marker of peroxisome proliferator action is the peroxisomal enzyme acyl CoA oxidase, which is elevated about ten fold in the livers of treated rodents. Additional peroxisome proliferator responsive genes include other peroxisomal β-oxidation enzymes and members of the cytochrome P450 IVA family. A peroxisome proliferator response element (PPRE), consisting of an almost perfect direct repeat of the sequence TGACCT spaced by a single base pair, has been identified in the upstream regulatory sequences of each of these genes. The retinoid X receptor (RXR) forms a heterodimer with PPAR and binds to the PPRE. Furthermore, the RXR ligand, 9-cis retinoic acid, enhances PPAR action. Retinoids may therefore modulate the action of peroxisome proliferators and PPAR may interfere with retinoid action, perhaps providing one mechanism to explain the toxicity of peroxisome proliferators. Interestingly, a variety of fatty acids can activate PPAR supporting the suggestion that fatty acids, or their acyl CoA derivatives, may be the natural ligands of PPAR and that the physiological role of PPAR is to regulate fatty acid homeostasis. Taken together, the discovery of PPAR has opened up new opportunities in understanding how lipid homeostasis is regulated, how the fibrate hypolipidaemic drugs may act and should lead to improvements in the assessment of human risk from peroxisome proliferators based upon a better understanding of their mechanism of action.     

Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models

Background & Aims

Non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH) are common clinico‐pathological conditions that affect millions of patients worldwide. In this study, the efficacy of saroglitazar, a novel PPARα/γ agonist, was assessed in models of NAFLD/NASH.

Methods & Results

HepG2 cells treated with palmitic acid (PA;0.75 mM) showed decreased expression of various antioxidant biomarkers (SOD1, SOD2, glutathione peroxidase and catalase) and increased expression of inflammatory markers (TNFα, IL1β and IL6). These effects were blocked by saroglitazar, pioglitazone and fenofibrate (all tested at 10μM concentration). Furthermore, these agents reversed PA‐mediated changes in mitochondrial dysfunction, ATP production, NFkB phosphorylation and stellate cell activation in HepG2 and HepG2‐LX2 Coculture studies. In mice with choline‐deficient high‐fat diet‐induced NASH, saroglitazar reduced hepatic steatosis, inflammation, ballooning and prevented development of fibrosis. It also reduced serum alanine aminotransferase, aspartate aminotransferase and expression of inflammatory and fibrosis biomarkers. In this model, the reduction in the overall NAFLD activity score by saroglitazar (3 mg/kg) was significantly more prominent than pioglitazone (25 mg/kg) and fenofibrate (100 mg/kg). Pioglitazone and fenofibrate did not show any improvement in steatosis, but partially improved inflammation and liver function. Antifibrotic effect of saroglitazar (4 mg/kg) was also observed in carbon tetrachloride‐induced fibrosis model.

Conclusions

Saroglitazar, a dual PPARα/γ agonist with predominant PPARα activity, shows an overall improvement in NASH. The effects of saroglitazar appear better than pure PPARα agonist, fenofibrate and PPARγ agonist pioglitazone.     

Oleoylethanolamide: The role of a bioactive lipid amide in modulating eating behaviour

Fatty acid ethanolamides are lipid mediators that regulate a plethora of physiological functions. One such bioactive lipid mediator, oleoylethanolamide (OEA), is a potent agonist of the peroxisome proliferator‐activated receptor‐alpha (PPAR‐α), which modulates increased expression of the fatty acid translocase CD36 that enables the regulation of feeding behaviour. Consumption of dietary fat rich in oleic acid activates taste receptors in the gut activating specific enzymes that lead to the formation of OEA. OEA further combines with PPAR‐α to enable fat oxidation in the liver, resulting in enhanced energy production. Evidence suggests that sustained ingestion of a high‐fat diet abolishes the anorexic signal of OEA. Additionally, malfunction of the enterocyte that transforms oleic acid produced during fat digestion into OEA might be responsible for reduced satiety and hyperphagia, resulting in overweight and obesity. Thus, OEA anorectic signalling may be an essential element of the physiology and metabolic system regulating dietary fat intake and obesity. The evidence reviewed in this article indicates that intake of oleic acid, and thereby the resulting OEA imparting anorexic properties, is dependent on CD36, PPAR‐α, enterocyte fat sensory receptors, histamine, oxytocin and dopamine; leading to increased fat oxidation and enhanced energy expenditure to induce satiety and increase feeding latency; and that a disruption in any of these systems will cease/curb fat‐induced satiety.     

Dietary conjugated linoleic acid increases PPAR gamma gene expression in adipose tissue of obese rat, and improves insulin resistance.

Conjugated linoleic acid (CLA) is a class of positional, geometric, conjugated dienoic isomers of linoleic acid. Dietary CLA supplementation has resulted in a dramatic decrease in body fat mass in mice. However, some but not all studies in mice and humans have found that CLA promoted insulin resistance, and there were conflicting reports on the effects of CLA on peroxisomal proliferator-activated receptor-gamma (PPAR gamma) activation and expression. The objective of present study was to investigate the effect of CLA on insulin resistance and its molecular mechanisms. Fifty male Wistar rats were randomly designed to the control, high-fat and high-fat with CLA (0.75, 1.50, and 3.00 g in per 100 g diet) groups. The effect of CLA on insulin sensitivity and the mechanism of resisting diabetes by CLA were investigated by RT-PCR assay. The results showed that supplementation with CLA significantly reduced body weight gain and white fat pad weight in the rats, the levels of plasma free fatty acids (FFA), triglycerides (TGs), cholesterin (TC), leptin, insulin and blood glucose concentration in the obese rats of CLA group were also decreased compared to the rats in the high-fat group. Dietary CLA increased the mRNA expression of PPAR gamma, fatty acid binding proteins (aP2), fatty acid transporter protein (FATP), acyl-CoA synthetase (ACS) and adiponectin in the adipose tissues of obese rats. The results suggest that CLA may ameliorate insulin resistance by activating PPAR gamma, and increasing the expression of PPAR gamma target genes such as ap2, FATP, FAT, and adiponectin in the white adipose tissue.     

The effects of oleoylethanolamide,an endogenous PPAR‐α agonist,on risk factors for NAFLD: A systematic review

Non‐alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. Recently, some novel compounds have been investigated for the prevention and treatment of NAFLD. Oleoylethanolamide (OEA), an endogenous PPAR‐α agonist, has exhibited a plethora of pharmacological properties for the treatment of obesity and other obesity‐associated metabolic complications. This systematic review was performed with a focus on the effects of OEA on the risk factors for NAFLD. PubMed, Scopus, Embase, ProQuest, and Google Scholar databases were searched up to December 2018 using relevant keywords. All articles written in English evaluating the effects of OEA on the risk factors for NAFLD were eligible for the review. The evidence reviewed in this article illustrates that OEA regulates multiple biological processes associated with NAFLD, including lipid metabolism, inflammation, oxidative stress, and energy homeostasis through different mechanisms. In summary, many beneficial effects of OEA have led to the understanding that OEA may be an effective therapeutic strategy for the management of NAFLD. Although a wide range of studies have demonstrated the most useful effects of OEA on NAFLD and the associated risk factors, further clinical trials, from both in vivo studies and in vitro experiments, are warranted to verify these outcomes.     

Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, reduces hepatic steatosis and lipid peroxidation in fatty liver Shionogi mice with hereditary fatty liver.

BACKGROUND AND AIMS: The fatty liver Shionogi (FLS) mouse, a unique model for nonalcoholic fatty liver disease (NAFLD), is an inbred strain that develops spontaneous hepatic steatosis without obesity or diabetes mellitus. Peroxisome proliferator-activated receptor (PPAR) alpha controls fatty acid metabolism. In the present study, we investigated the effect of fenofibrate, a PPARalpha agonist, on hepatic steatosis in FLS mice. METHODS: Thirteen-week-old FLS mice were fed a diet with 0.1% fenofibrate (w/w) for 12 days. The degree of hepatic steatosis was estimated by histological examination and hepatic triglyceride levels. Expression levels of genes involved in fatty acid turnover, including Acox1, Cpt1a, Fabp1, Acadl, and Acadm, were determined by Northern blot analyses. We measured levels of lipid peroxidation, glutathione, and anti-oxidative enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, in the liver. RESULT: Treatment of FLS mice with fenofibrate improved hepatic steatosis by activating expression of genes involved in fatty acid turnover and decreased hepatic lipid peroxidation. Fenofibrate increased the activity of catalase by upregulating its mRNA levels. CONCLUSION: Fenofibrate, which is currently used in therapy of hyperlipidemia, might also be useful for treating patients with NAFLD even in cases where NAFLD is not associated with obesity or diabetes mellitus.     

Fatty acyl CoA synthetase activity in normal and atherosclerotic rabbit aortic tissue.

The activity of fatty acyl CoA synthetase and fatty acyl CoA:cholesterol acyltransferase was determined in microsomal fractions from normal and atherosclerotic rabbit aortic tissue. No change in fatty acyl CoA synthetase activity was observed as a result of cholesterol feeding in contrast to the several-fold increase in the activity of fatty acyl CoA:cholesterol acyltransferase seen in atherosclerotic tissue. Inhibition of both enzymes was observed when clofibrate, or the tetrahydronapthyl analog of this drug were added in vitro. The inhibitory effects were most pronounced on the fatty acyl CoA:cholesterol acyltransferase.     

Role of selective peroxisome proliferator‐activated receptor modulators in managing cardiometabolic disease: tale of a roller‐coaster

Atherogenic dyslipidaemia is a hypertriglyceridaemic phenotype, associated with increased plasma concentrations of small, dense low‐density lipoprotein (sdLDL) particles, triglyceride‐rich lipoproteins (TRLs) and non‐high‐density lipoprotein cholesterol (non‐HDL‐C), and low HDL particles. Atherogenic dyslipidaemia commonly accompanies several metabolic disorders including type 2 diabetes, metabolic syndrome, non‐alcoholic fatty liver disease (NAFLD) and obesity, and increases the risk of cardiovascular disease (CVD). Statins significantly lower plasma LDL‐cholesterol and CVD risk, but their efficacy in correcting hypertriglyceridaemia is limited. Untreated hypertriglyceridaemia may partly account for residual risk of CVD in patients on statin treatment. Activators of peroxisome proliferator‐activated receptor (PPAR) α are more effective in correcting TRL and HDL metabolism than statins. A dual PPARα/δ agonist (GFT‐505) may have additional benefits on hepatic insulin sensitivity, steatosis and fibrosis. Selective PPAR modulators (SPPARMs) have the potential of increasing therapeutic specificity, while reducing unwanted off‐target effects. This review provides a summary of findings from randomized controlled trials of the efficacy of fenofibrate (as the most widely used PPARα agonist) and novel selective PPARα (ABT‐335 and k‐877), PPARα/δ (GFT‐505), PPARδ (MBX‐8025 and GW501516) and PPARγ (INT131) agonists in the treatment of atherogenic dyslipidaemia and NAFLD.     

肉毒碱对酒精性心肌病心肌代谢和重构的影响及机制研究

目的 观察肉毒碱对酒精性心肌病(ACM)发病过程中代谢紊乱及心脏重构的防治机制及作用.方法 将实验动物分为3组:酒精(A)组、酒精/药物(B)组和对照(C)组.检测血清游离脂肪酸(FFA)、肉毒碱含量,测定心肌组织过氧化物酶体增殖物激活受体(PPAR)α和PPARγ、类维甲酸受体(RXR)a、肉毒碱棕榈酰转移酶Ⅰ(CPT-Ⅰ)、中链脂酰辅酶A脱氢酶(MCAD)的mRNA和蛋白表达.结果 (1)与C组比较,A组和B组FFA含量升高,肉毒碱含量下降,PPARα、RXRα、CPT-Ⅰ和MCAD的mRNA和蛋白表达量随ACM进展逐渐减少,A组比B组更为显著(P<0.05).(2)在2和4个月时,A、B和c组PPA脚mRNA和蛋白表达差异无统计学意义(P>0.05).6个月后B组PPARγ表达量增加,A组表达降低,和C组比较,差异均具有统计学意义(A比C,P<0.01;B比C,P<0.05).结论 ACM进展中发生心肌能量代谢紊乱和心脏重构,肉毒碱可能通过上调PPARα、RXRα、CPT-Ⅰ和MCAD改善心肌代谢障碍,通过上调PPARγ预防心脏重构.