Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet

Abstract

The methionine choline-deficient (MCD) diet results in liver injury similar to human nonalcoholic steatohepatitis (NASH). The aims of this study were to define mechanisms of MCD-induced steatosis in insulin-resistant db/db and insulin-sensitive db/m mice. MCD-fed db/db mice developed more hepatic steatosis and retained more insulin resistance than MCD-fed db/m mice. Both subcutaneous and gonadal fat were reduced by MCD feeding: gonadal fat decreased by 23% in db/db mice and by 90% in db/m mice. Weight loss was attenuated in the db/db mice, being only 13% compared with 35% in MCD-fed db/db and db/m mice, respectively. Both strains had upregulation of hepatic fatty acid transport proteins as well as increased hepatic uptake of [ 14 C]oleic acid: 3-fold in db/m mice (P , 0.001) and 2-fold in db/db mice (P , 0.01) after 4 weeks of MCD feeding. In both murine strains, the MCD diet reduced triglyceride secretion and downregulated genes involved in triglyceride synthesis. Therefore, increased fatty acid uptake and decreased VLDL secretion represent two important mechanisms by which the MCD diet promotes intrahepatic lipid accumulation in this model. Feeding the MCD diet to diabetic rodents broadens the applicability of this model for the study of human NASH.-Rinella, M. E., M. S. Elias, R. R. Smolak, T. Fu, J. Borensztajn, and R. M. Green. Mechanisms of hepatic steatosis in mice fed a lipogenic methionine choline-deficient diet.

Silibinin improves hepatic and myocardial injury in mice with nonalcoholic steatohepatitis

“…Mitochondrial respiratory chain (MRC) activities was determined as previously described [24]. Briefly, liver tissues (50-70 mg) were homogenized with 15 vol of 20 mmol/L KP buffer, pH 7.4, and centrifuged at 800 × g for 10 min.…”

“…In order to investigate this issue, we used db/db mice fed a methionine-choline deficient (MCD) diet, a model combining the features of the metabolic syndrome with the histological pattern of NASH [23,24]. In fact, db/db mice fed an MCD diet do partially conserve increased visceral adiposity and an insulin resistant phenotype, while developing hepatocellular injury [24].…”

Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture

“…43,44 MCD-fed rats develop NASH and hepatic insulin resistance, but the animals lose visceral and peripheral fat, lose weight and do not experience peripheral insulin resistance. 45 These features might limit the relevance of findings in this model for the understanding of human disease.…”

Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-Fed db/db mice

“…In db/db mice, in which obesity drives increased delivery of FFA to the liver, it has been demonstrated that an MCD diet exacerbates steatosis dramatically. [14][15][16] We assessed hepatic steatosis by H&E staining, liver/body weight (BW) ratio, epididymal fat/BW ratio and liver triglyceride content at the end of 8 weeks of treatment. An MCD diet induced further intra-hepatic lipid accumulation in db/db mice but MR16-1 treatment had no effect on hepatic steatosis (Figure 4a).…”

“…13 Feeding db/db mice with an MCD diet induces steatohepatitis and liver fibrosis within only 8 weeks, providing a useful small animal model for progressive, obesityrelated NASH. [14][15][16] We have reported recently that blockade of IL-6 signaling by neutralizing antibody against the IL-6 receptor (MR16-1), which is a specific antagonist of the mouse IL-6 receptor, enhanced liver steatosis but improved liver injury in wildtype lean mice fed with an MCD diet. 17,18 We interpreted this result as indicating that excess IL-6 produced by an MCD diet may have exerted an effect as a pro-inflammatory cytokine, leading to the progression of NASH.…”