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

Am J Physiol Gastrointest Liver Physiol. 2016 May 1;310(9):G726-38. doi: 10.1152/ajpgi.00436.2015. Epub 2016 Mar 11.


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.

Keywords: Perilipin 2; lipid droplets; methionine-choline-deficient diet; nonalcoholic steatohepatitis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Caspase 1 / genetics
  • Caspase 1 / metabolism
  • Choline Deficiency / complications
  • Cytokines / genetics
  • Cytokines / metabolism
  • Lipoproteins, LDL / metabolism
  • Liver / metabolism*
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism*
  • 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


  • CCAAT-Enhancer-Binding Proteins
  • Cytokines
  • Lipoproteins, LDL
  • Perilipin-2
  • Phosphatidylcholines
  • Plin2 protein, mouse
  • Triglycerides
  • Methionine
  • PEMT protein, mouse
  • Phosphatidylethanolamine N-Methyltransferase
  • Caspase 1