期刊
CELLS
卷 10, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/cells10051016
关键词
perilipin; lipid droplet; autophagy; adipose tissue triglyceride lipase; non-alcoholic fatty liver disease
类别
资金
- Robert C. and Veronica Atkins Foundation [8050-5100-097-02S, DK108722, P30DK046200, R21HD098056]
- [T32DK06032]
The data suggest that protection against NAFLD in the absence of hepatic PLIN2 is driven by the integrated actions of both ATGL and lipophagy, with increased autophagy contributing to enhanced cellular fatty acid oxidation in PLIN2(LKO) hepatocytes. Inhibiting either ATGL or autophagy blunted the increased FA oxidation, while combined inhibition of both pathways reduced FA oxidation to the same extent as treatment with either inhibitor alone.
An imbalance in the storage and breakdown of hepatic lipid droplet (LD) triglyceride (TAG) leads to hepatic steatosis, a defining feature of non-alcoholic fatty liver disease (NAFLD). The two primary cellular pathways regulating hepatic TAG catabolism are lipolysis, initiated by adipose triglyceride lipase (ATGL), and lipophagy. Each of these processes requires access to the LD surface to initiate LD TAG catabolism. Ablation of perilipin 2 (PLIN2), the most abundant lipid droplet-associated protein in steatotic liver, protects mice from diet-induced NAFLD. However, the mechanisms underlaying this protection are unclear. We tested the contributions of ATGL and lipophagy mediated lipolysis to reduced hepatic TAG in mice with liver-specific PLIN2 deficiency (PLIN2(LKO)) fed a Western-type diet for 12 weeks. We observed enhanced autophagy in the absence of PLIN2, as determined by ex vivo p62 flux, as well as increased p62- and LC3-positive autophagic vesicles in PLIN2(LKO) livers and isolated primary hepatocytes. Increased levels of autophagy correlated with significant increases in cellular fatty acid (FA) oxidation in PLIN2(LKO) hepatocytes. We observed that inhibition of either autophagy or ATGL blunted the increased FA oxidation in PLIN2(LKO) hepatocytes. Additionally, combined inhibition of ATGL and autophagy reduced FA oxidation to the same extent as treatment with either inhibitor alone. In sum, these studies show that protection against NAFLD in the absence of hepatic PLIN2 is driven by the integrated actions of both ATGL and lipophagy.
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