title: 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: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan, 44919, Korea.
authors: Kwang-Youn
authors: KY
authors: Kim
authors: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan, 44919, Korea.
authors: Hyun-Jun
authors: HJ
authors: Jang
authors: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan, 44919, Korea.
authors: Yong Ryoul
authors: YR
authors: Yang
authors: Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Cheomdan-ro 70, Daegu 41062, Korea.
authors: Kwang-Il
authors: KI
authors: Park
authors: UNIST Central Research Facilities, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan, 44919, Korea.
authors: JeongKon
authors: J
authors: Seo
authors: School of Medicine, Gyeongsang National University, Jinju, 52727, Korea.
authors: Il-Woo
authors: IW
authors: Shin
authors: Department of Animal Science, Chonnam National University, Gwangju 61186 South Korea.
authors: Tae-Il
authors: TI
authors: Jeon
authors: Department of Microbiology &Immunology, Pusan National University School of Medicine, Yangsan 50612, Korea.
authors: Soon-Cheol
authors: SC
authors: Ahn
authors: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan, 44919, Korea.
authors: Pann-Ghill
authors: PG
authors: Suh
authors: Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, FL 32827, USA.
authors: Timothy F
authors: TF
authors: Osborne
authors: School of Life Sciences, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan, 44919, Korea.
authors: Young-Kyo
authors: YK
authors: Seo
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage; D000071182:Autophagosomes / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D000069438:Ezetimibe / Q000008:administration & dosage; D054522:Group VI Phospholipases A2 / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D008148:Lovastatin / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D014280:Triglycerides; D008148:Lovastatin; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse; D000069438:Ezetimibe