title: Liver-specific loss of Perilipin 2 alleviates diet-induced hepatic steatosis, inflammation, and fibrosis.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan;
authors.forename: Charles P
authors.initials: CP
authors.lastname: Najt
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan;
authors.forename: Subramanian
authors.initials: S
authors.lastname: Senthivinayagam
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan;
authors.forename: Mohammad B
authors.initials: MB
authors.lastname: Aljazi
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan;
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Fader
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan;
authors.forename: Sandra D
authors.initials: SD
authors.lastname: Olenic
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan;
authors.forename: Julienne R L
authors.initials: JR
authors.lastname: Brock
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, Michigan; and.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Lydic
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan; Department of Chemistry, Michigan State University, East Lansing, Michigan.
authors.forename: A Daniel
authors.initials: AD
authors.lastname: Jones
authors.affiliation: Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan; atshaves@msu.edu.
authors.forename: Barbara P
authors.initials: BP
authors.lastname: Atshaves
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002796:Choline Deficiency / Q000150:complications; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D000070780:Perilipin-2 / Q000235:genetics* / Q000378:metabolism; D010713:Phosphatidylcholines / Q000378:metabolism; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D016207:Cytokines; D008077:Lipoproteins, LDL; D000070780:Perilipin-2; D010713:Phosphatidylcholines; C000602983:Plin2 protein, mouse; D014280:Triglycerides; D008715:Methionine; C559160:PEMT protein, mouse; D050918:Phosphatidylethanolamine N-Methyltransferase; D020170:Caspase 1
keywords: Perilipin 2; lipid droplets; methionine-choline-deficient diet; nonalcoholic steatohepatitis