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

Abstract

Secondary hyperlipidemia is a major cardiovascular risk factor in individuals with type 2 diabetes. Increased hepatic production of apolipoprotein B (apoB)-containing lipoproteins contributes to the elevated plasma levels, but the mechanism is poorly understood. Recent results have established that microsomal triglyceride transfer protein (MTP) is rate limiting for the assembly and secretion of apoB-containing lipoproteins. To better understand the mechanism of type 2 diabetes-associated hyperlipidemia, we quantified hepatic MTP mRNA levels, hepatic microsomal triglyceride transfer activity, and in vivo triglyceride secretion from the liver in two diabetic mouse models. Obese diabetic (ob/ob) mice had 45% higher (P ‫؍‬ 0.006) hepatic MTP mRNA levels, 54% higher (P < 0.0001) microsomal triglyceride transfer activity, and 70% higher (P < 0.0001) in vivo triglyceride secretion rates compared with ob/؉ control mice. In contrast, in lean streptozotocin-treated diabetic mice, hepatic MTP mRNA levels were unchanged, whereas microsomal triglyceride transfer activity and in vivo triglyceride secretion rates were marginally decreased. These studies suggest that obesity-induced type 2 diabetes in mice confers increases in hepatic MTP expression and secretion of triglyceride-rich lipoproteins. High blood glucose and altered hepatic expression of sterol regulatory element binding protein genes play a minor role in this diabetic response. Diabetes 51: 1233-1239, 2002 T he incidence and prevalence of type 2 diabetes are rapidly rising (1). Individuals with type 2 diabetes have an increased risk of cardiovascular disease, which is closely associated with elevation of the plasma levels of apolipoprotein B (apoB)-containing VLDL and LDL (2,3). Metabolic labeling studies have indicated that the increased plasma levels of VLDL and LDL in individuals with diabetes are caused, at least in part, by increased hepatic secretion of apoB-containing lipoproteins (4,5). Hence, a better understanding of the factors in patients with type 2 diabetes that mediate increased lipoprotein secretion from the liver could potentially lead to rational therapeutic strategies to prevent cardiovascular disease in this patient group.During the past 5 years, it has become evident that microsomal triglyceride transfer protein (MTP) is rate limiting for the production of apoB-containing VLDL (6 -10). MTP is an exclusively intracellular protein (6). Its principal role is to transfer lipids onto the apoB polypeptide in the endoplasmic reticulum of lipoprotein-secreting cells (6). Reduction of the MTP activity in animals by MTP inhibitor drugs (7) or genetic manipulations (11,12) lowers plasma lipoprotein levels, whereas adenoviral overexpression of an MTP cDNA in mouse liver in vivo increases hepatic secretion of triglyceride-rich apoB-containing lipoproteins (13,14).Studies of cultured liver cells suggest that insulin and glucose reduce the expression of the MTP gene (15); the MTP gene promoter region contains a putative insulinresponsive element (16). Also, r...

Increased Expression of Adhesion Molecules in Uremic Atherosclerosis in Apolipoprotein-E–Deficient Mice

“…All samples were analyzed in tetraplicate on separate TLC plates. The precision and accuracy of this assay have been reported elsewhere (19,20).…”

Coordinate Transcriptional Repression of Liver Fatty Acid-binding Protein and Microsomal Triglyceride Transfer Protein Blocks Hepatic Very Low Density Lipoprotein Secretion without Hepatosteatosis

“…In ob/ob diabetic mice, adenovirus-mediated expression of PGC-1␤ and Foxa2 induced MTP expression, suggesting a mechanism through which insulin blocks VLDL assembly/secretion (59). It has been demonstrated that Foxa2 is completely excluded from the nucleus of ob/ob mice (60), whereas both MTP expression and VLDL assembly/secretion are increased (61). Furthermore, PGC-1␤-mediated increase in MTP expression was retained in the ob/ob mice indicating that induction of MTP transcription can occur via Foxa2-independent mechanisms (59).…”

Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver

“…3C, top). However, a decrease, 22,23 increase, 24 or no change 25 in VLDL secretion have also been reported in OB Ϫ/Ϫ mice, and the reason for the discrepant observations is unknown. Nevertheless, SHP deletion led to both slower TG clearance and higher rates of hepatic lipid secretion, which may be associated with the increased serum TG levels in OB Ϫ/Ϫ /SHP Ϫ/Ϫ mice.…”