Impact of Microsomal Triglyceride Transfer Protein (MTP) in Preventing Hepatic Apoptosis

Several studies have revealed that lower hepatic expression of microsomal triglyceride transfer protein (MTP) plays an important role in the development of nonalcoholic steatohepatitis (NASH). The aim of this study was to clarify the relationship between MTP and apoptosis using Fatty Liver Shionogi mice (FLS). We checked the phenotypes including the degree of apoptosis and performed molecular biological examinations in 16- and 48-week-old FLS and C57BL/6J mice (B6). The influence of MTP induction on apoptosis was examined using vector-mediated hepatic expression of MTP. The degree of hepatic apoptosis indicated by TUNEL staining, the gene expression of Bax and Bcl-2 and the protein expression of Bax and cleaved caspase3 were markedly increased in 48-week-old FLS compared to 48-week-old B6. TUNEL-positive cells and the protein expression of Bax, Bcl-2 and cleaved caspase3 were markedly increased in 48- week-old FLS compared to 16-week-old FLS. Hepatocyte apoptosis was increased in 16-week-old FLS with increased TUNEL-positive cells and upregulation of the protein expression of Bax compared to those in 16-week-old B6. The pAKT/AKT ratio was decreased in 48-week-old FLS compared to 16-week-old FLS and 48-week-old B6. Hepatic induction of MTP resulted in not only amelioration of steatosis as well as insulin resistance, but also prevention of the progression to hepatic apoptosis via inhibition of the expression of Bax and cleaved caspase3 accompanied by restoration of the pAKT/AKT ratio. Our findings suggested that MTP might play a pivotal role in preventing the progression to hepatic apoptosis in the development of NASH via improvement of hepatic insulin resistance.