MCD-induced steatohepatitis is associated with hepatic adiponectin resistance and adipogenic transformation of hepatocytes.
OBJECTIVE
In these studies, we tested the hypothesis that increased lipid intake would exacerbate the severity of nutritional steatohepatitis.


METHODS
C57Bl/6J mice were fed methionine-and-choline deficient (MCD) diets containing 20% (high) or 5% (low) fat by weight for 3 weeks and compared to lipid-matched controls.


RESULTS
MCD feeding increased serum ALT levels and induced hepatic steatosis, lobular inflammation and ballooning degeneration of hepatocytes, irrespective of dietary fat content. Hepatic triglyceride accumulation was similar between high and low-fat MCD-fed mice, but lipoperoxide levels were approximately 3-fold higher in the high-fat MCD-fed animals. Serum adiponectin levels increased in MCD-fed mice, although to a lesser extent in high-fat fed animals. AMPK phosphorylation was correspondingly increased in muscle of MCD-fed mice, but hepatic AMPK phosphorylation decreased, and there was little evidence of PPAR alpha activation, suggesting impaired adiponectin action in the livers of MCD-fed animals. Hepatocyte PPAR gamma mRNA levels increased in MCD-fed mice, and were associated with increased aP2 expression, indicating adipogenic transformation of hepatocytes.


CONCLUSIONS
Increased dietary lipid intake did not alter steatohepatitis severity in MCD-fed mice despite increased lipoperoxide accumulation. Instead, steatohepatitis was associated with impaired hepatic adiponectin action, and adipogenic transformation of hepatocytes in both low and high-fat MCD-fed mice.
ANU Medical School, Australian National University at The Canberra Hospital, Canberra, ACT, Australia.
Claire Z
CZ
Larter
Matthew M
MM
Yeh
Jacqueline
J
Williams
Kim S
KS
Bell-Anderson
Geoffrey C
GC
Farrell
D000091162:AMP-Activated Protein Kinase Kinases; D017667:Adipocytes / Q000378:metabolism / Q000473:pathology; D050156:Adipogenesis / Q000502:physiology; D052242:Adiponectin / Q000097:blood / Q000502:physiology*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002796:Choline Deficiency / Q000150:complications*; D004041:Dietary Fats; D004195:Disease Models, Animal; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006505:Hepatitis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D008054:Lipid Peroxides / Q000378:metabolism; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D052242:Adiponectin; D004041:Dietary Fats; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D008054:Lipid Peroxides; D047495:PPAR gamma; D014280:Triglycerides; D008715:Methionine; D000410:Alanine Transaminase; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases