SREBP-2/PNPLA8 axis improves non-alcoholic fatty liver disease through activation of autophagy

Sci Rep. 2016 Oct 21:6:35732. doi: 10.1038/srep35732.

Abstract

Dysregulated autophagy is associated with steatosis and non-alcoholic fatty liver disease (NAFLD), however the mechanisms connecting them remain poorly understand. Here, we show that co-administration of lovastatin and ezetimibe (L/E) significantly reverses hepatic triglyceride accumulation concomitant with an increase in SREBP-2 driven autophagy in mice fed a high-fat diet (HFD). We further show that the statin mediated increase in SREBP-2 directly activates expression of patatin-like phospholipase domain-containing enzyme 8 (PNPLA8) gene, and PNPLA8 associates with autophagosomes and is associated with a decrease in cellular triglyceride. Moreover, we show that over-expression of PNPLA8 dramatically decreases hepatic steatosis through increased autophagy in hepatocytes of HFD-fed mice. Live-cell imaging analyses also reveal that PNPLA8 dynamically interacts with LC3 and we suggest that the SREBP-2/PNPLA8 axis represents a novel regulatory mechanism for lipid homeostasis. These data provide a possible mechanism for the reported beneficial effects of statins for decreasing hepatic triglyceride levels in NAFLD patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticholesteremic Agents / administration & dosage
  • Autophagosomes / metabolism
  • Autophagy / drug effects
  • Autophagy / physiology
  • Cells, Cultured
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Ezetimibe / administration & dosage
  • Group VI Phospholipases A2 / metabolism*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage
  • Lovastatin / administration & dosage
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Non-alcoholic Fatty Liver Disease / pathology
  • Signal Transduction / drug effects
  • Sterol Regulatory Element Binding Protein 2 / metabolism*
  • Triglycerides / metabolism

Substances

  • Anticholesteremic Agents
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Srebf2 protein, mouse
  • Sterol Regulatory Element Binding Protein 2
  • Triglycerides
  • Lovastatin
  • Group VI Phospholipases A2
  • Pla2g6 protein, mouse
  • Ezetimibe