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

Kwang Youn Kim, Hyun Jun Jang, Yong Ryul Yang, Kwang Il Park, Jeong Kon Seo, Il Woo Shin, Tae Il Jeon, Soon Cheol Ahn, Pann Ghill Suh, Timothy F. Osborne, Young Kyo Seo

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number35732
JournalScientific reports
Volume6
DOIs
StatePublished - Oct 21 2016
Externally publishedYes

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    Kim, K. Y., Jang, H. J., Yang, Y. R., Park, K. I., Seo, J. K., Shin, I. W., Jeon, T. I., Ahn, S. C., Suh, P. G., Osborne, T. F., & Seo, Y. K. (2016). SREBP-2/PNPLA8 axis improves non-alcoholic fatty liver disease through activation of autophagy. Scientific reports, 6, [35732]. https://doi.org/10.1038/srep35732