Key intestinal genes involved in lipoprotein metabolism are downregulated in dyslipidemic men with insulin resistance

Patrick Couture,André J Tremblay,Isabelle Kelly,Valéry Lemelin,Arnaud Droit,Benoît Lamarche

doi:10.1194/jlr.m040071

Abstract

Insulin resistance (IR) is associated with elevated plasma levels of triglyceride-rich lipoproteins (TRLs) of intestinal origin. However, the mechanisms underlying the overaccumulation of apolipoprotein (apo)B-48-containing TRLs in individuals with IR are not yet fully understood. This study examined the relationships between apoB-48-containing TRL kinetics and the expression of key intestinal genes and proteins involved in lipid/lipoprotein metabolism in 14 obese nondiabetic men with IR compared with 10 insulin-sensitive (IS) men matched for waist circumference. The in vivo kinetics of TRL apoB-48 were assessed using a primed-constant infusion of L-[5,5,5-D₃]leucine for 12 h with the participants in a constantly fed state. The expression of key intestinal genes and proteins involved in lipid/lipoprotein metabolism was assessed by performing real-time PCR quantification and LC-MS/MS on duodenal biopsy specimens. The TRL apoB-48 pool size and production rate were 102% (P < 0.0001) and 87% (P = 0.01) greater, respectively, in the men with IR versus the IS men. On the other hand, intestinal mRNA levels of sterol regulatory element binding factor-2, hepatocyte nuclear factor-4α, and microsomal triglyceride transfer protein were significantly lower in the men with IR than in the IS men. These data indicate that IR is associated with intestinal overproduction of lipoproteins and significant downregulation of key intestinal genes involved in lipid/lipoprotein metabolism.

Highlights

Insulin resistance (IR) is associated with elevated plasma levels of triglyceride-rich lipoproteins (TRLs) of intestinal origin
We investigated the relationships between intestinally derived apoB-48-containing lipoprotein kinetics and the expression of key intestinal genes and proteins involved in lipid and lipoprotein metabolism in nondiabetic men with IR compared with insulin-sensitive (IS) men
The in vivo kinetics of TRL apoB-48 in the fed state were assessed using a stable isotope enrichment technique, and gene expression along with protein mass levels were assessed by conducting real-time PCR quantification and LC-MS/MS, respectively, on duodenal biopsy specimens from participants with IR and IS control participants in the fasted state

Summary

Introduction

Insulin resistance (IR) is associated with elevated plasma levels of triglyceride-rich lipoproteins (TRLs) of intestinal origin. This study examined the relationships between apoB-48containing TRL kinetics and the expression of key intestinal genes and proteins involved in lipid/lipoprotein metabolism in 14 obese nondiabetic men with IR compared with 10 insulin-sensitive (IS) men matched for waist circumference. Intestinal mRNA levels of sterol regulatory element binding factor-2, hepatocyte nuclear factor-4␣, and microsomal triglyceride transfer protein were significantly lower in the men with IR than in the IS men. These data indicate that IR is associated with intestinal overproduction of lipoproteins and significant downregulation of key intestinal genes involved in lipid/lipoprotein metabolism.— Couture, P., A.

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Conclusion