Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance

Abstract

The common complications in obesity and type 2 diabetes include hepatic steatosis and disruption of glucose-glycogen homeostasis, leading to hyperglycemia. Fatty acid translocase (FAT/CD36), whose expression is inducible in obesity, is known for its function in fatty acid uptake. Previous work by us and others suggested that CD36 plays an important role in hepatic lipid homeostasis, but the results have been conflicting and the mechanisms were not well understood. In this study, by using CD36-overexpressing transgenic (CD36Tg) mice, we uncovered a surprising function of CD36 in regulating glycogen homeostasis. Overexpression of CD36 promoted glycogen synthesis, and as a result, CD36Tg mice were protected from fasting hypoglycemia. When challenged with a high-fat diet (HFD), CD36Tg mice showed unexpected attenuation of hepatic steatosis, increased very low-density lipoprotein (VLDL) secretion, and improved glucose tolerance and insulin sensitivity. The HFD-fed CD36Tg mice also showed decreased levels of proinflammatory hepatic prostaglandins and 20-hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictive and proinflammatory arachidonic acid metabolite. We propose that CD36 functions as a protective metabolic sensor in the liver under lipid overload and metabolic stress. CD36 may be explored as a valuable therapeutic target for the management of metabolic syndrome. Individuals with metabolic syndrome or type 2 diabetes are susceptible to nonalcoholic fatty liver disease (1) and disruption of hepatic glucose and glycogen homeostasis (2). Hepatic steatosis is defined as an excess accumulation of fat in hepatocytes. Previous reports suggested that fatty acid translocase (FAT/CD36) plays an important role in hepatic lipid homeostasis (3-6). CD36 is a multiligand class B scavenger receptor with high affinity for lipids and lipid-containing ligands. CD36 is known for its lipid uptake function in macrophages, skeletal muscle, and the heart. However, the role of CD36 in hepatic lipid metabolism is still not well understood, and the available evidence is often conflicting, partly due to the lack of a reliable in vivo liver-specific gain-of-function model to specifically evaluate the function of CD36 in the liver.The basal expression of CD36 in the liver is low; however, it is highly inducible by a high-fat diet (HFD) (3). The hepatic expression of CD36 is under the transcriptional control of the nuclear receptors: liver X receptor (LXR), pregnane X receptor (PXR), peroxisome proliferator-activated receptors (PPARs), and the aryl hydrocarbon receptor (AhR) (4). Some studies have suggested that hepatic CD36, by functioning as a fatty acid transporter, has a role in the pathogenesis of hepatic steatosis (3), obesity (7, 8), and age-related hepatic steatosis (5). Furthermore, we and others reported that induction of CD36 was a common factor in fatty liver following the activation of LXR and PXR (6, 9). On the other hand, recent reports suggested that CD36 signaling might actually be beneficial in preventing fatty live...

Defining lipid mediators of insulin resistance: controversies and challenges

“…These findings are not without their contradictions: the overexpression of FATP1 in skeletal muscle, for example, channels lipids to oxidation and does not predispose to diet-induced IR (Holloway et al 2011). Overexpression of the FA transporter/scavenger receptor CD36 in muscle and liver has also been shown to attenuate genetic and diet-induced IR via enhancement of oxidative capacity (Ibrahimi et al 1999, Héron-Milhavet et al 2004, Garbacz et al 2016).…”

20-HETE in the regulation of vascular and cardiac function

“…A few studies noted that 20-HETE levels in blood or urine are correlated with body to mass ratio (BMI) in humans (Barden et al, 2007; Issan et al, 2013; Peterson et al, 2016; Tsai et al, 2009; Ward et al, 2006). There are also a few studies demonstrating that 20-HETE levels are increased during the course of high fat feeding and in metabolic syndrome animals (Garbacz et al, 2016; Joseph et al, 2017; Soler et al, 2018; Theken et al, 2012). However, the role of 20-HETE in the pathogenesis of obesity and its associated cardiometabolic conditions including, hypertension, insulin resistance and vascular dys-function, is unclear.…”

PDK4‐Deficiency Reprograms Intrahepatic Glucose and Lipid Metabolism to Facilitate Liver Regeneration in Mice

“…Cd36 deletion in hepatocytes reduced high‐fat diet (HFD)‐induced hepatic steatosis, decreased hepatic FA uptake, and improved whole‐body insulin sensitivity . However, Cd36 transgenic mice challenged with HFD also showed attenuation of hepatic steatosis and improved glucose tolerance and insulin sensitivity . Thus, as a lipid sensor for energy balance, the intriguing pathophysiological role of CD36 needs to be further elucidated.…”