Open AccessLipidomic and transcriptomic analysis of western diet-induced nonalcoholic steatohepatitis (NASH) in female Ldlr -/- mice
Author(s) -
Manuel García-Jaramillo,
Melinda H. Spooner,
Christiane V. Löhr,
Carmen P. Wong,
Weijian Zhang,
Donald Β. Jump
Publication year - 2019
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0214387
Subject(s) - nonalcoholic fatty liver disease , steatohepatitis , fatty liver , medicine , steatosis , endocrinology , biology , lipotoxicity , cancer research , insulin resistance , diabetes mellitus , disease
Background Nonalcoholic fatty liver disease ( NAFLD ) is the most common chronic liver disease worldwide, particularly in obese and type 2 diabetic individuals. NAFLD ranges in severity from benign steatosis to nonalcoholic steatohepatitis ( NASH ); and NASH can progress to cirrhosis, primary hepatocellular carcinoma ( HCC ) and liver failure. As such, NAFLD has emerged as a major public health concern. Herein, we used a lipidomic and transcriptomic approach to identify lipid markers associated with western diet ( WD ) induced NASH in female mice. Methods Female mice (low-density lipoprotein receptor null ( Ldlr-/- ) were fed a reference or WD diet for 38 and 46 weeks. Transcriptomic and lipidomic approaches, coupled with statistical analyses, were used to identify associations between major NASH markers and transcriptomic & lipidomic markers. Results The WD induced all major hallmarks of NASH in female Ldlr -/- mice, including steatosis (SFA, MUFA, MUFA-containing di- and triacylglycerols), inflammation ( TNFα) , oxidative stress (Ncf2) , and fibrosis (Col1A) . The WD also increased transcripts associated with membrane remodeling (LpCat) , apoptosis & autophagy ( Casp1 , CtsS ), hedgehog ( Taz ) & notch signaling ( Hey1 ), epithelial-mesenchymal transition (S1004A) and cancer ( Gpc3 ). WD feeding, however, suppressed the expression of the hedgehog inhibitory protein ( Hhip ), and enzymes involved in triglyceride catabolism ( Tgh/Ces3 , Ces1g) , as well as the hepatic abundance of C 18-22 PUFA-containing phosphoglycerolipids (GpCho, GpEtn, GpSer, GpIns). WD feeding also increased hepatic cyclooxygenase (Cox1 & 2) expression and pro-inflammatory ω6 PUFA-derived oxylipins (PGE2), as well as lipid markers of oxidative stress (8-iso-PGF2α). The WD suppressed the hepatic abundance of reparative oxylipins (19, 20-DiHDPA) as well as the expression of enzymes involved in fatty epoxide metabolism ( Cyp2C , Ephx ). Conclusion WD-induced NASH in female Ldlr -/ - mice was characterized by a massive increase in hepatic neutral and membrane lipids containing SFA and MUFA and a loss of C 18-22 PUFA-containing membrane lipids. Moreover, the WD increased hepatic pro-inflammatory oxylipins and suppressed the hepatic abundance of reparative oxylipins. Such global changes in the type and abundance of hepatic lipids likely contributes to tissue remodeling and NASH severity.