TRANSCRIPTIONAL REGULATION OF HUMAN AND HAMSTER MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN GENES - CELL-TYPE-SPECIFIC EXPRESSION AND RESPONSETO METABOLIC REGULATORS

In order to characterize the molecular mechanisms that dictate microso mal triglyceride transfer protein (MTP) gene transcription in human an d hamster, two species with similar plasma lipoprotein profiles, the M TP gene promoters were cloned, sequenced, and functionally characteriz ed by transient transfection analysis. The results presented in this r eport indicate that the 5' ends of human and hamster MTP genes share s imilar structural features. The promoter sequences are well conserved and consist of similar functional elements. Transient transfection ana lysis of MTP promoter-driven luciferase gene expression showed that th e promoter is active in liver and intestinal cells but not in epitheli al cells, consistent with endogenous MTP gene expression. The -123 to -85 bp region of the human promoter is critical for the expression and contains the consensus recognition sequences for liver cell-specific factors HNF-1 and HNF-4 and activator protein AP-1. The pro meter cont ains a modified sterol response element and a negative insulin respons e element. The human promoter activity is positively regulated by chol esterol and negatively regulated by insulin. From the functional analy sis of MTP promoters, it is concluded that the elements that regulate the cell type-specific expression in human and hamster are well conser ved and that insulin and cholesterol can regulate the activity of the MTP promoter in opposite directions.