Integrated action of autophagy and adipose tissue triglyceride lipase ameliorates diet-induced hepatic steatosis in liver specific PLIN2 knockout mice

Authors: GRIFFIN, JOHN - Tufts University; BEJARANO-FERNANDEZ, ELOY - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; WANG, XIANG-DONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; GREENBERG, ANDREW - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Cells
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/22/2021
Publication Date: 4/25/2021
Citation: Griffin, J., Bejarano-Fernandez, E., Wang, X., Greenberg, A.S. 2021. Integrated action of autophagy and adipose tissue triglyceride lipase ameliorates diet-induced hepatic steatosis in liver specific PLIN2 knockout mice. Cells. 10(5):1016. https://doi.org/10.3390/cells10051016.
DOI: https://doi.org/10.3390/cells10051016

Interpretive Summary: Aging and obesity are associated with increased accumulation of fat in the liver which can promote liver disease. In this paper we demonstrate that reduced expression of the protein, perilipin 2, in mice fed a high fat diet reduces accumulation of fat in the liver.

Technical Abstract: An imbalance in the storge and breakdown of hepatic lipid droplet (LD) triglyceride (TAG) leads to hepatic steatosis, a defining feature of non-alcoholic fatty liver dieases (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 test the contributions of ATGL and lipophagy mediated lipolysis to reduced hepatic TAG in mice with liver-specific PLIN2 deficiency (PLIN2LKO) 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 PLIN2LKO livers and isolated primary hepatocytes. Increased levels of autophagy correlated with significant increases in cellular fatty acid (FA) oxidation in PLIN2LKO hepatocytes. We observed that inhibition of either autophagy or ATGL blunted the increased FA oxidation in PLIN2LKO 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.