Liver-specific loss of Perilipin 2 alleviates diet-induced hepatic steatosis, inflammation, and fibrosis

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 310; no. 9; pp. G726 - G738
• Main Authors: Najt, Charles P., Senthivinayagam, Subramanian, Aljazi, Mohammad B., Fader, Kelly A., Olenic, Sandra D., Brock, Julienne R. L., Lydic, Todd A., Jones, A. Daniel, Atshaves, Barbara P.
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.05.2016
• Subjects: Animals; Caspase 1 - genetics; Caspase 1 - metabolism; CCAAT-Enhancer-Binding Proteins - genetics; CCAAT-Enhancer-Binding Proteins - metabolism; Choline Deficiency - complications; Cytokines - genetics; Cytokines - metabolism; Diet; Hepatitis; Inflammation; Lipids; Lipoproteins, LDL - metabolism; Liver - metabolism; Liver and Biliary Tract Physiology/Pathophysiology; Liver Cirrhosis - etiology; Liver Cirrhosis - genetics; Liver Cirrhosis - metabolism; Liver diseases; Methionine - deficiency; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Perilipin-2 - genetics; Perilipin-2 - metabolism; Phosphatidylcholines - metabolism; Phosphatidylethanolamine N-Methyltransferase - metabolism; Triglycerides - metabolism; nonalcoholic steatohepatitis; Perilipin 2; lipid droplets; methionine-choline-deficient diet
• ISSN: 0193-1857; 1522-1547; 1522-1547
• DOI: 10.1152/ajpgi.00436.2015

Hepatic inflammation and fibrosis are key elements in the pathogenesis of nonalcoholic steatohepatitis (NASH), a progressive liver disease initiated by excess hepatic lipid accumulation. Lipid droplet protein Perilipin 2 (Plin2) alleviates dietary-induced hepatic steatosis when globally ablated; however, its role in the progression of NASH remains unknown. To investigate this further, we challenged Plin2 liver-specific knockout mice (designated L-KO) and their respective wild-type (WT) controls with a methionine-choline-deficient (MCD) diet for 15 days to induce a NASH phenotype of increased hepatic triglyceride levels through impaired phosphatidylcholine (PC) synthesis and very-low-density lipoprotein (VLDL) secretion. Results on liver weights, body weights, fat tissue mass, and histology in WT and L-KO mice fed the MCD diet revealed signs of hepatic steatosis, fibrosis, and inflammation; however, these effects were blunted in L-KO mice. In addition, levels of PC and VLDL were unchanged, and hepatic steatosis was reduced in L-KO mice fed the MCD diet, due in part to an increase in remodeling of PE to PC via the enzyme phosphatidylethanolamine N-methyltransferase (PEMT). These mice also exhibited decreased hepatic expression of proinflammatory markers cyclooxygenase 2, IL-6, TNF-α, IL-1β, and reduced expression of endoplasmic reticulum (ER) stress proteins C/EBP homologous protein and cleaved caspase-1. Taken together, these results suggest that Plin2 liver-specific ablation alleviates diet-induced hepatic steatosis and inflammation via a PEMT-mediated mechanism that involves compensatory changes in proteins involved in phospholipid remodeling, inflammation, and ER stress that work to alleviate diet-induced NASH. Overall, these findings support a role for Plin2 as a target for NASH therapy.