Abstract
Peroxisome proliferative associated receptor δ（PPARδ）belongs to the nuclear receptor family and has been found to involve in metabolic diseases. Although PPARδ is known to attenuate hepatic lipid deposition, its mechanism remain unclear. Here, we show that PPARδ is a potent stimulator of hepatic autophagic flux. Expression levels of PPARδ and autophagy markers were detected in liver tissues of obese and lean mice by western blot. Hepatic PPARδ expression decreased in obese mice in comparison to lean control, and the same findings were acquired in autophagy-related proteins (ATGs). Pharmacological or adenovirus-mediated promotion of PPARδ was applied in obese transgenetic db/db and high fat diet-fed mice. Using genetic, pharmacological, and metabolic approaches, we demonstrate that PPARδ reduces intrahepatic lipid content and stimulates β-oxidation in liver by an autophagy-lysosomal pathway. These results provide a novel insight into PPARδ's lipolytic actions through autophagy in liver and display its potential beneficial effects in NAFLD. Funding Statement: This study was supported by the National Natural Science Foundation of China (No. 81570719, 81670797 81471074, 81770863, 81500660), partly supported by Key Laboratory for Endocrine and Metabolic Diseases, Chinese Ministry of Public Health (No. 1994DP131044), Ministry of Science & Technology Innovation Fund and projects (No.2011YQ030114), the Basic Important Program (No.10JC141100), the Sector Funds of Ministry of Health (No. 201002002), and the National Key New Drug Creation and Manufacturing Program by Declaration of Interests: The authors declare that they have no conflict of interests. Ethics Approval Statement: The animal protocol were reviewed and approved by the Animal Care Committee of Shanghai Jiao Tong University School of Medicine.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is recognised as the leading cause of chronic liver disease in adults and children[1], with histological characteristics ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH) and cirrhosis; some cases even develop into end-stage liver disease and hepatocellular carcinoma[2,3]
We show that Peroxisome proliferator-activated receptor δ (PPARδ) activation-induced fatty acid oxidation (FAO) mediated by the autophagy–lysosomal pathway is the central mechanism for improving NAFLD
The expression of lipogenic proteins, including fatty acid synthase (FAS), carbohydrate-responsive element binding protein (ChREBP) and stearoyl-CoA desaturase 1 (SCD1), was upregulated in model mice compared to control mice (Fig. 1a–c), which is consistent with increased lipid aggregation in the liver of obese mice[19]
Summary
Non-alcoholic fatty liver disease (NAFLD) is recognised as the leading cause of chronic liver disease in adults and children[1], with histological characteristics ranging from simple fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH) and cirrhosis; some cases even develop into end-stage liver disease and hepatocellular carcinoma[2,3]. NAFLD appears to be highly associated with obesity and diabetes. NAFLD is characterised by the progressive accumulation of triglycerides (TGs) in hepatocytes, which could result from increased free fatty acid (FFA) uptake into the liver, impaired lipid catabolism or enhanced de novo lipogenesis[4,5]. Agonists are well established in therapeutic areas related to lipid and glucose metabolism, such as T2DM, obesity and dyslipidaemia[10,11,12]. PPARα is one of the most abundantly expressed nuclear receptors in the liver[12,13]. PPARα and its agonists have hepatoprotective effects in rodent models of NAFLD/NASH. Fibrates and other available PPARα agonists have shown no beneficial effects on steatosis in human studies[14]. PPARα expression is low in the human liver relative to the rodent liver, and Official journal of the Cell Death Differentiation Association
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