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.

Breaking fat: The regulation and mechanisms of lipophagy

“…Based on previous work showing that ATGL promotes the activity of SIRT1 [18], a major driver of autophagy [19], additional studies show that SIRT1 mediates the effects of ATGL on promoting autophagy/lipophagy. This work is also supported by studies showing that PNPLA5 and PNPLA8, members of the patatin-like phospholipase domain-containing protein family that also contain ATGL (PNPLA2), promote autophagy/lipophagy in a variety of cell types [20,21]. Regarding PNPLA5, Dupont et al suggest that diacylglycerol generated by PNPLA5 is critical for autophagosomal membrane synthesis and may influence membrane curvature and, thus, protein trafficking.…”

“…Knockdown of SREBP-2 activates autophagy genes during sterol depletion and is responsible for autophagosome formation to promote lipid droplet turnover [85]. A subsequent study revealed that SREBP-2 promotes the expression of PNPLA8, which facilitates lipophagy and prevents hepatic steatosis [21]. These studies would suggest that SREBP-2, in response to reduced intracellular cholesterol levels, promotes lipophagy as a means to increase cholesterol levels, in addition to directly promoting the expression of cholesterol synthesis genes.…”

Patatin‐like phospholipases in microbial infections with emerging roles in fatty acid metabolism and immune regulation by Apicomplexa

“…However, PNPLA3 and PNPLA5 show the opposite pattern, reminiscent of genes involved in lipogenesis, such as FAS (Baulande et al, 2001;Liu et al, 2017). The insulindependent activation of PNPLA3 is mediated by the sterol regulatory element-binding protein (SREBP) transcription factors to promote triglyceride synthesis (Kim et al, 2016). ATGL, PNPLA3 and PNPLA5 contain two distinct C-terminal lipid droplet targeting motifs responsible for their recruitment to lipid droplets (Murugesan et al, 2013).…”

“…Dashed lines indicate indirect pathways. with less energy consumption than uptake or de novo synthesis (Kim et al, 2016). The fatty acids released by lipid hydrolysis can provide twice as much ATP as carbohydrates relative to their mass and are important in energy storage, especially in adipose tissue.…”

“…PNPLA8 is also regulated by the SREBP family, but PNPLA8 associates with mitochondria and peroxisomes and has both PLA 1 and PLA 2 activity. PNPLA8 activation induces lipid droplet mobilization through autophagy to provide the cell with new lipids faster and with less energy consumption than uptake or de novo synthesis (Kim et al ., ). The fatty acids released by lipid hydrolysis can provide twice as much ATP as carbohydrates relative to their mass and are important in energy storage, especially in adipose tissue.…”