Endocrine Abstracts

Background: In mice, a methionine-choline deficient diet (MCDD) causes steatohepatitis and hepatic insulin resistance. In contrast, a simple choline-deficient diet (CDD) causes liver fat accumulation without steatohepatitis, insulin resistance or weight loss. We hypothesised that differences in liver and adipose fatty acid metabolism underlie the contrasting predisposition to steatohepatitis and hepatic insulin resistance.

Methods: C57Bl6 mice (male, aged 14 weeks) were fed CDD, MCDD, or supplemented control diet (CS) for 2 weeks. In different groups of animals (n=6–8), ¹³C enrichment of plasma and liver fatty acids was measured by GCMS following ¹³C₄-palmitate infusion (to measure free fatty acid (FFA) turnover) or ¹³C₂-acetate dietary labelling (quantifying de novo lipogenesis (DNL)), and hepatic triglyceride (TG) export was assessed following i.v. tyloxapol. Results are means±S.E.M. for CS, CDD and MCDD respectively. *P<0.05, **P<0.01, ***P<0.001 by one way ANOVA.

Results: CDD induced liver steatosis while MCDD produced a centrilobular steatohepatitis. MCDD but not CDD led to weight loss (body weight 28.89±0.89 vs 26.79±0.52 vs ***21.63±0.53 g), with smaller subcutaneous and perigonadal adipose depots. However, no difference was found in serum TGs or FFA, or in the rate of appearance of FFA between groups (data not shown). Mass isotopomer distribution analysis of incorporation of ¹³C₂-acetate into hepatic TGs showed increased absolute DNL synthesis rates only in the MCDD group (1.41±0.33 vs 2.16±0.35 vs **3.61±0.16 μmol/day). Hepatic TG export was reduced by approximately *25% and **50% in CDD and MCDD respectively.

Conclusions: Steatohepatitis in MCDD is associated with a greater increase in DNL and more profound impairment of hepatic TG export than in CDD. Reduced fatty acid release from the liver, rather than enhanced peripheral lipolysis, appears to explain weight loss on MCDD. Progressive steatohepatitis and hepatic insulin resistance in MCDD rather than CDD is likely due to toxic effects of intracellular FFAs in the liver.