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

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.

• Authors: Kwang-Youn Kim, Hyun-Jun Jang, Yong Ryoul Yang, Kwang-Il Park, JeongKon Seo, Il-Woo Shin, Tae-Il Jeon, Soon-Cheol Ahn, Pann-Ghill Suh, Timothy F Osborne, Young-Kyo Seo
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 35732 (10 21 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 27767079 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Animals
• Anticholesteremic Agents (administration & dosage)
• Autophagosomes (metabolism)
• Autophagy (drug effects, 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, metabolism, pathology)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (administration & dosage)
• Lovastatin (administration & dosage)
• Male
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (drug therapy, metabolism, pathology)
• Signal Transduction (drug effects)
• Sterol Regulatory Element Binding Protein 2 (metabolism)
• Triglycerides (metabolism)