Abstract 290: Key Intestinal Genes Involved in Lipoprotein Metabolism Are Downregulated in Insulin-Resistant Males

Abstract

Recent studies indicate that insulin-resistance (IR) is associated with elevated levels of triglyceride-rich lipoproteins (TRL), including apoB-48-containing TRL of intestinal origin, in both the fasted and post-prandial states. This is of interest because elevated levels of intestine-derived lipoproteins are associated with increased cardiovascular disease risk. However, the mechanisms underlying the overaccumulation of apoB-48-containing TRL in IR have not been fully characterized in human. Therefore, the objective of this study was to examine the relationships between apoB-48-containing TRL kinetics and expression of key intestinal genes involved in lipid and lipoprotein metabolism in nondiabetic, IR males compared with insulin-sensitive (IS) males matched for age and waist circumference. A total of 30 nondiabetic caucasian males were chosen for extremes of insulin sensitivity (14 IR and 16 IS subjects) and matched for age and waist circumference. In vivo kinetics of TRL apoB-48 were assessed using a primed-constant infusion of L-[5,5,5-D3]leucine for 12h in the fed state in all subjects. Expression of key intestinal genes involved in lipid and lipoprotein metabolism was compared by real-time PCR quantification in duodenal biopsy specimens from IR and IS participants taken in the fasted state. TRL apoB-48 pool size (PS) and production rate (PR) were increased by 105% (P<0.0001) and 45% (P=0.03), respectively in IR subjects compared with IS subjects. Expression of the nuclear transcription factors SREBP-2, SREBP1-C and HNF4α was significantly reduced by 31%, 28% and 25%, respectively in IR subjects. Similarly, many key genes involved in cholesterol, fatty acid, triglyceride and lipoprotein metabolism were significantly downregulated in IR individuals. In IR participants, intestinal expression of HMG CoAR, ACC1, SCD1, DGAT2, apoB and MTP was significantly reduced compared with IS subjects. Intestinal MTP expression was inversely correlated with TRL apoB-48 PS (r=-0.50, P=0.005) and PR (r=-0.32, P=0.07). These data suggest that IR is associated with intestinal overproduction of lipoproteins and downregulation of key intestinal genes involved in lipid/lipoprotein metabolism. Downregulation of these genes in the fasted state could represent an adaptive response to IR state.