FATTY LIVER-DISEASE
; MASS-SPECTROMETRIC ANALYSIS
; HEPATIC STEATOSIS
; DOCOSAHEXAENOIC ACID
; METABOLIC SYNDROME
; AMERICAN ASSOCIATION
; PRACTICE GUIDELINE
; ARACHIDONIC-ACID
; NATURAL-HISTORY
; SEX-DIFFERENCES
WOS学科分类:
Multidisciplinary Sciences
WOS研究方向:
Science & Technology - Other Topics
英文摘要:
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 (LdIr(-/-)) 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(-/-)r mice, including steatosis (SFA, MUFA, MUFA-containing di- and triacylglycerols), inflammation (TNF alpha), oxidative stress (Ncf2), and fibrosis (Coll A). The WD also increased transcripts associated with membrane remodeling (LpCat), apoptosis & autophagy (Caspl, 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, Ces1 g), as well as the hepatic abundance of C18-22 PUFA-containing phosphoglycerolipids (GpCho, GpEtn, GpSer, Gpins). WD feeding also increased hepatic cyclooxygenase (Cox1 & 2) expression and pro-inflammatory omega 6 PUFA-derived oxylipins (PGE2), as well as lipid markers of oxidative stress 8-iso-PGF2 alpha). 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 LdIr(-/-) mice was characterized by a massive increase in hepatic neutral and membrane lipids containing SFA and MUFA and a loss of C18-22 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.
1.Oregon State Univ, Sch Biol & Populat Hlth Sci, Nutr Program, Corvallis, OR 97331 USA 2.Oregon State Univ, Linus Pauling Inst, Corvallis, OR 97331 USA 3.Oregon State Univ, Dept Chem, Gilbert Hall 153, Corvallis, OR 97331 USA 4.Oregon State Univ, Carlson Coll Vet Med, Anat Pathol, Corvallis, OR 97331 USA
Recommended Citation:
Garcia-Jaramillo, Manuel,Spooner, Melinda H.,Lohr, Christiane V.,et al. Lipidomic and transcriptomic analysis of western diet-induced nonalcoholic steatohepatitis (NASH) in female LdIr(-/-) mice[J]. PLOS ONE,2019-01-01,14(4)