Hepatocyte CYP2E1 Overexpression and Steatohepatitis Lead to Impaired Hepatic Insulin Signaling

Abstract

Insulin resistance and increased cytochrome P450 2E1 (CYP2E1) expression are both associated with and mechanistically implicated in the development of nonalcoholic fatty liver disease. Although currently viewed as distinct factors, insulin resistance and CYP2E1 expression may be interrelated through the ability of CYP2E1-induced oxidant stress to impair hepatic insulin signaling. To test this possibility, the effects of in vitro and in vivo CYP2E1 overexpression on hepatocyte insulin signaling were examined. CYP2E1 overexpression in a hepatocyte cell line decreased tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 in response to insulin. CYP2E1 overexpression was also associated with increased inhibitory serine 307 and 636/639 IRS-1 phosphorylation. In parallel, the effects of insulin on Akt activation, glycogen synthase kinase 3, and FoxO1a phosphorylation, and glucose secretion were all significantly decreased in CYP2E1 overexpressing cells. This inhibition of insulin signaling by CYP2E1 overexpression was partially c-Jun N-terminal kinase dependent. In the methionine-and choline-deficient diet mouse model of steatohepatitis with CYP2E1 overexpression, insulin-induced IRS-1, IRS-2, and Akt phosphorylation were similarly decreased. These findings indicate that increased hepatocyte CYP2E1 expression and the presence of steatohepatitis result in the down-regulation of insulin signaling, potentially contributing to the insulin resistance associated with nonalcoholic fatty liver disease.

A Choline-Deficient Diet Exacerbates Fatty Liver but Attenuates Insulin Resistance and Glucose Intolerance in Mice Fed a High-Fat Diet

“…However, MCDD also causes significant weight loss (18), and the relative influence of weight loss and liver fat accumulation has not been addressed. Moreover, in mice with steatohepatitis induced by MCDD, insulin receptor substrate phosphorylation in the liver was impaired, rather than enhanced, after a bolus of insulin administered into the portal vein (19), possibly because the inflammatory signals associated with hepatitis might confound effects on insulin sensitivity. A choline-deficient diet (CDD) also reliably induces fatty liver in rodents in the absence of methionine deficiency, although the mechanisms are less clear and may differ from those in MCDD (20).…”

Cytochrome P450 2E1 participation in the pathogenesis of experimental metabolic syndrome in guinea pigs

“…In crease in CYP2E1 expression and free radicals pro duction results in oxidative damage to the liver cells. This leads to progressive carbohydrate metabolism disorders and progressive tissue and organ dama ges [26]. Thus the regulation of CYP2E1 expression might be an effective mechanism for the correction of systemic CYP2E1dependent oxidative stress upon metabolic syndrome.…”

Life Style-Related Diseases of the Digestive System: Gene Expression in Nonalcoholic Steatohepatitis Patients and Treatment Strategies

“…It is likely to be worsened by aging and environmental factors such as consumption of highly saturated fats (15). Whether hepatic insulin resistance causes cellular injury and inflammation in the liver or results from both inflammation and steatosis is a key question in unraveling the pathogenesis of NASH (16). One molecular mechanism of insulin resistance is intracellular accumulation of fatty acids and their metabolites that activates protein kinase C (17,18).…”

“…One molecular mechanism of insulin resistance is intracellular accumulation of fatty acids and their metabolites that activates protein kinase C (17,18). Protein kinase C catalyzes serine/ threonine phosphorylation of the insulin receptor substrate (IRS)-1 and 2, and hepatic over-expression of cytochrome P450 (CYP) 2E1 in NASH patients creates oxidative stress associated with impaired insulin receptor signaling (16). Tumor necrosis factor alpha (TNFα), another candidate molecule in the transition from steatosis to steatohepatitis, is liberated by the adipose tissues of obese persons (19) and could worsen hepatic insulin resistance via activation of an inhibitor of kappaB kinase (IKK-β) or c-Jun N-terminal kinase.…”