Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice.
OBJECTIVE
We previously reported that steatohepatitis develops in obese, hypercholesterolemic, diabetic foz/foz mice fed a high-fat (HF) diet for 12 months. We now report earlier onset of steatohepatitis in relation to metabolic abnormalities, and clarify the roles of dietary fat and bodily lipid partitioning on steatosis severity, liver injury and inflammatory recruitment in this novel non-alcoholic steatohepatitis (NASH) model.


METHODS
Foz/foz (Alms1 mutant) and wild-type (WT) mice were fed a HF diet or chow, and metabolic characteristics and liver histology were studied at 2, 6, 12 and 24 weeks.


RESULTS
After 12 weeks HF-feeding, foz/foz mice were obese and diabetic with approximately 70% reduction in serum adiponectin. Hepatomegaly developed at this time, corresponding to a plateau in adipose expansion and increased adipose inflammation. Liver histology showed mild inflammation and hepatocyte ballooning as well as steatosis. By 24 weeks, HF-fed foz/foz mice developed severe steatohepatitis (marked steatosis, alanine aminotransferase elevation, ballooning, inflammation, fibrosis), whereas dietary and genetic controls showed only simple steatosis. While steatosis was associated with hepatic lipogenesis, indicated by increased fatty acid synthase activity, steatohepatitis was associated with significantly higher levels of CD36, indicating active fatty acid uptake, possibly under the influence of peroxisome proliferator-activated receptor-gamma.


CONCLUSIONS
In mice genetically predisposed to obesity and diabetes, HF feeding leads to restriction of adipose tissue for accommodation of excess energy, causing lipid partitioning into liver, and transformation of simple steatosis to fibrosing steatohepatitis. The way in which HF feeding 'saturates' adipose stores, decreases serum adiponectin and causes hepatic inflammation in steatohepatitis may provide clues to pathogenesis of NASH in metabolic syndrome.
Liver Research Group, ANU Medical School, Canberra Hospital, Garran, Australian Capital Territory 2605, Australia.
Claire Z
CZ
Larter
Matthew M
MM
Yeh
Derrick M
DM
Van Rooyen
Narci C
NC
Teoh
John
J
Brooling
Jing Yun
JY
Hou
Jacqueline
J
Williams
Matthew
M
Clyne
Christopher J
CJ
Nolan
Geoffrey C
GC
Farrell
D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001692:Biological Transport; D015415:Biomarkers / Q000097:blood; D018955:CD36 Antigens / Q000378:metabolism; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins / Q000235:genetics; D048909:Diabetes Complications / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004041:Dietary Fats / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D006937:Hypercholesterolemia / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009765:Obesity / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D052242:Adiponectin; C499919:Adipoq protein, mouse; C510001:Alms1 protein, mouse; D015415:Biomarkers; D018955:CD36 Antigens; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D005227:Fatty Acids; D014280:Triglycerides