Association between microsomal triglyceride transfer protein gene polymorphism and the biological features of liver steatosis in patients with Type II diabetes

Abstract

The term non-alcoholic steatohepatitis (NASH) describes liver disease histologically similar to alcoholic liver disease occurring in patients without any history of excessive alcohol consumption [1,2]. Two main histological criteria are necessary for the diagnosis of NASH: fatty degeneration and inflammation or fibrosis. The latter criteria distinguishes NASH from simple steatosis which has a non-progressive course [3]. In western countries, NASH is a major cause of increased liver enzymes, next to alcohol consumption and hepatitis C [2]. It is frequently associated with obesity (40 %), Type II diabetes (20 %) and hyperlipidaemia (20 %) We therefore assessed the association between a functional polymorphism in the promoter region of MTP gene (±493 G/T) and the biological features of steatohepatitis in Type II diabetic patients. Methods. We studied 271 patients with Type II diabetes. Determination of ±493 G/T polymorphism was made by PCR-RFLP. Increased liver enzymes were used as surrogates of liver steatosis and alanine aminotransferase concentration was the outcome variable for the multivariate analysis. Liver ultrasonography was available for a subgroup of patients with newly diagnosed diabetes.Results. The proportion of patients with increased alanine aminotransferase was higher in GG than in GT and TT subgroups (23 %, 11 % and 6 %, respectively, p = 0.01). Additionally, patients with high alanine aminotransferase concentrations were more likely to be young (p = 0.01), male (p = 0.001), obese (p = 0.04) and have low HDL-cholesterol (p = 0.01).In multivariate analysis, the MTP genotype was independently associated with alanine aminotransferase concentration (p = 0.0023) as well as sex and body mass index but not HDL-cholesterol. Conclusion/interpretation. The ±493 G/T MTP gene polymorphism is associated with biological surrogates of steatohepatitis in patients with Type II diabetes. The G allele which is responsible for a decrease in MTP gene transcription is prone to increase the intrahepatic triglycerides content, conferring by this a genetic susceptibility for steatohepatitis. [Diabetologia (2000) 43: 995±999]

Dietary Habits and Their Relations to Insulin Resistance and Postprandial Lipemia in Nonalcoholic Steatohepatitis

“…An interesting candidate is microsomal Tg transfer protein, which plays a key role in assembly and secretion of chylomicrons and VLDL by the intestine and the liver, respectively. 30 Actually, a reduced activity of microsomal Tg transfer protein, as a consequence of different gene polymorphism, has been recently associated with the development of hepatic steatosis in diabetic subjects 31 and can be part of the genetic susceptibility to steatohepatitis.…”

Hepatic Expression of Microsomal Triglyceride Transfer Protein and In Vivo Secretion of Triglyceride-Rich Lipoproteins Are Increased in Obese Diabetic Mice

“…Even though simple mild hepatic steatosis often has a benign course in nondiabetic individuals, ϳ20% of individuals with type 2 diabetes develop nonalcoholic steatohepatitis that ultimately results in cirrhosis in 20 -30% of the cases (42). Recent observations propose a link between hepatic MTP gene expression levels and development of nonalcoholic steatohepatitis: indexes of nonalcoholic steatohepatitis in individuals with type 2 diabetes are more frequent in carriers of the G allele of the Ϫ493 G/T polymorphism in the MTP promoter than in carriers of the T allele (43). The G allele confers a 50% lower promoter activity compared with the T allele (44).…”

Nonalcoholic Steatohepatitis: Summary of An Aasld Single Topic Conference

“…In fact, the knockout of MTTP in mice is embryonically lethal. Lesser defects, such as a G/T polymorphism at position Ϫ493 of the human MTTP promoter, have been linked to an increased risk for hepatic steatosis in diabetes 111 and increased sensitivity of the liver to endotoxin. 112 Even with normal processing of the nascent apoB100 protein, most of the translational product undergoes degradation in the endoplasmic reticulum and only a small fraction reaches the circulation, an observation that suggests ample overproduction of apoB100 in the basal state.…”