Seven weeks of Western diet in apolipoprotein-E-deficient mice induce metabolic syndrome and non-alcoholic steatohepatitis with liver fibrosis

Abstract

Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation and fibrosis, which might progress to cirrhosis. Human NASH is associated with metabolic syndrome (MS). Currently, rodent NASH models either lack significant fibrosis or MS. ApoE−/− mice are a MS model used in cardiovascular research. The aim of this work was to establish and characterise a novel mouse NASH model with significant fibrosis and MS. ApoE−/− and wild-type mice (wt) were fed either a western-diet (WD), methionine-choline-deficient-diet (MCD) or normal chow. Liver histology, RT-PCR, hepatic hydroxyproline content, triglycerides and cholesterol levels, and fasting glucose levels assessed hepatic steatosis, inflammation and fibrosis. Further, portal pressure was measured invasively, and kidney pathology was assessed by histology. ApoE−/− mice receiving WD showed abnormal glucose tolerance, hepatomegaly, weight gain and full spectrum of NASH including hepatic steatosis, fibrosis and inflammation, with no sign of renal damage. MCD-animals showed less severe liver fibrosis, but detectable renal pathological changes, besides weight loss and unchanged glucose tolerance. This study describes a murine NASH model with distinct hepatic steatosis, inflammation and fibrosis, without renal pathology. ApoE−/− mice receiving WD represent a novel and fast model with all characteristic features of NASH and MS well suitable for NASH research.

Updates on Dietary Models of Nonalcoholic Fatty Liver Disease: Current Studies and Insights

“…However, two studies mentioned previously that did not include added sugar were not noted to lead to hepatic inflammation in WT mice 44,47 indicating the significant role sugar may play in the inflammatory process. In the study by Dorn et al mice were fed a HFD with cholesterol and sucrose (15% pork lard, 15% beef tallow, 4% palmitic acid, 4% stearic acid, 0.2% cholesterol and 30% sucrose) for 12 weeks and developed hepatic inflammation as indicated by increased inflammatory cell inflitration 53 .…”

“…In the study by Schierwagen et al mice fed a HFD (21% of fat from coconut oil and 19.5% from casein) supplemented with high cholesterol (1.25% of diet) for 7 weeks hepatic fibrosis did not occur 44 . In contrast, in the study by Dorn et al a HFD with cholesterol and sucrose lead to NASH as well as the early stages of hepatic fibrosis 53 .…”

“…Four studies showed that mice fed an MCD diet for as few as 2 weeks but up to 7 weeks developed no change or had decreased levels of serum triglycerides, cholesterol, and glucose 27,37,38,44 . In contrast, in a study by Kim et al mice that were fed an MCD diet for 4 weeks developed elevated serum triglycerides and total cholesterol levels 22 .…”

“…In humans, dietary cholesterol is not a major contributor to serum cholesterol levels; however, the American Heart Association still recommends that humans consume less than 300 mg of dietary cholesterol per day 61–63 . In a study by Schierwagen et al mice were fed a HFD (21% of fat from coconut oil and 19.5% from casein) supplemented with high cholesterol (1.25% of diet) for 7 weeks and mice subsequently showed increased intrahepatic triglyceride levels, indicative of hepatic steatosis 44 .…”

“…In a study by Lian et al, WT mice that were fed a HFD diet (containing 60% calories from fat) for 16 weeks had increased weight gain, which is an indicator of NAFLD and metabolic syndrome 60 . In a study by Schierwagen et al, a high fat diet (21% of fat from coconut oil and 19.5% from casein) supplemented with high cholesterol (1.25% of diet) was given to WT mice for 7 weeks 44 . Further, mice fed this diet developed increased levels of serum glucose but did not have significantly increased body weight 44 .…”