DENND5B Regulates Intestinal Triglyceride Absorption and Body Mass

Scott M Gordon,Iftikhar J Kullo,Leslie G Biesecker,Xiao Fan,Lita A Freeman,Milton Pryor,Alan T Remaley,Zhihong Yang,Edward B Neufeld

doi:10.1038/s41598-019-40296-0

Abstract

Regulation of lipid absorption by enterocytes can influence metabolic status in humans and contribute to obesity and related complications. The intracellular steps of chylomicron biogenesis and transport from the Endoplasmic Reticulum (ER) to the Golgi complex have been described, but the mechanisms for post-Golgi transport and secretion of chylomicrons have not been identified. Using a newly generated Dennd5b−/− mouse, we demonstrate an essential role for this gene in Golgi to plasma membrane transport of chylomicron secretory vesicles. In mice, loss of Dennd5b results in resistance to western diet induced obesity, changes in plasma lipids, and reduced aortic atherosclerosis. In humans, two independent exome sequencing studies reveal that a common DENND5B variant, p.(R52K), is correlated with body mass index. These studies establish an important role for DENND5B in post-Golgi chylomicron secretion and a subsequent influence on body composition and peripheral lipoprotein metabolism.

Highlights

Current, pharmacological interventions for obesity have largely been aimed at suppressing appetite and blockade of fat absorption[4]
Measurement of plasma lipids in Dennd5b−/− mice revealed a significant reduction in plasma total cholesterol (TC) and phospholipids (PL) but not triglyceride (TG) (Fig. 1B–D)
Perhaps DENND5B performs more than one function with influence on metabolism. These data demonstrate a role for Dennd5b in murine enterocyte chylomicron secretion

Summary

Introduction

Pharmacological interventions for obesity have largely been aimed at suppressing appetite and blockade of fat absorption[4]. The pathways and molecular machinery involved in fatty acid absorption, re-esterification of TG, chylomicron biogenesis and endoplasmic reticulum (ER) to Golgi transport have been well characterized[5]. The importance of these pathways in human energy metabolism is demonstrated in patients with pathogenic variants in APOB, MTP, and SAR1B (formerly SARA2)[6]. (GEF) activity toward Rab GTPases and the Rab specificity of DENN proteins varies among family members[9] Based on this function, it has been proposed that DENN proteins are involved in the regulation of intracellular vesicular transport pathways. We tested the hypothesis that DENND5B is important in human lipid metabolism using two independent exome sequencing cohorts

Methods

Results

Conclusion