CD36 deletion reduces VLDL secretion, modulates liver prostaglandins, and exacerbates hepatic steatosis in ob/ob mice

Abstract

This article is available online at http://www.jlr.org novo FA synthesis or de novo lipogenesis (DNL), decreased FA oxidation, and reduced secretion of VLDLs ( 1, 2 ).CD36 is a class B scavenger receptor that plays an important role in several pathways of FA utilization. The protein is expressed in many cell types, including lingual taste bud cells, enterocytes, adipocytes, myocytes, and immune cells. On taste bud cells, CD36 is important for FA recognition and fat perception ( 3, 4 ). In skeletal muscle, heart, and adipose tissue, CD36 facilitates tissue FA uptake and utilization ( 5, 6 ). In the small intestine, it is important for chylomicron secretion ( 7 ) and for FA-induced release of secretin and cholecystokinin ( 8 ). In the liver, CD36 is expressed on endothelial, parenchymal, and Kupffer cells ( 9 ). Basal expression of liver CD36 is low but increases in experimental models of hepatic steatosis, such as genetic obesity and highfat feeding ( 10, 11 ) or following activation of the prosteatotic transcription factors liver X receptor (LXR), pregnane X receptor (PXR), and aryl hydrocarbon receptor (AHR) by xenobiotics, bacteria, or cytokines ( 12 ). Mice fed a highfat diet have increased liver CD36 expression associated with enhanced hepatic FA uptake and TG accumulation, and these are prevented by CD36 deletion ( 11 ). Interestingly, however, the prosteatotic effects of a high-fructose diet, which enhances DNL and TG accumulation in the liver ( 13 ), are exacerbated by CD36 deletion ( 14 ).In humans with nonalcoholic fatty liver disease (NAFLD), hepatic CD36 positively correlates with liver fat content ( 15 ), but its relationship to output of VLDL suggests that its impact on hepatic FA metabolism might not be limited to enhancing FA fl ux and TG accumulation. NAFLD is Abstract Recent findings described the role of CD36-mediated signaling in regulating cellular calcium and the release of various bioactive molecules, including the prostaglandins, neurotransmitters, cholecystokinin, and secretin. Here we document the role of CD36 in the secretion of hepatic VLDL. CD36 deletion resulted in 60% suppression of VLDL output in vivo, and VLDL secretion was reduced in vitro using incubated liver slices. The effect of CD36 deletion was mediated by enhancing formation of hepatic prostaglandins D2, F2, and E2. Treatment of CD36-defi cient slices with inhibitors of cyclooxygenases reversed the reduction in triglyceride secretion. We also examined the effect of CD36 deletion on the obesity-associated spontaneous steatosis of the ob/ob mouse that is driven by enhanced de novo lipogenesis. Homozygous ob/ob mice lacking CD36 ( ob-CD36 ؊ / ؊ ) were generated and studied for hepatic triglyceride accumulation and VLDL secretion. Livers of ob/ob mice were steatotic as expected and had 5-fold more CD36 on Kupffer cells and hepatocytes. CD36 deletion exacerbated the steatosis by impairing hepatic triglyceride and apoB secretion through increasing prostaglandin levels. These fi ndings suggest an unappreciated role of CD36 in reg...

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

“…CD36 signaling has been suggested to play a role in the liberation of AA and subsequent formation of PGs (37). Increased levels of hepatic PGs can negatively affect the hepatic export of VLDL (10,38). We found that HFD-fed CD36Tg mice had significantly reduced hepatic PGE2, PGF2␣, and 6-keto-PGF1 levels compared to their WT controls and the CD36Tg-plus-Dox group (Fig.…”

“…The suppression of PGs may have contributed to increased VLDL secretion, because PGs are known to inhibit VLDL secretion from the liver (10,50). The suppressed PG production and increased VLDL secretion in our CD36Tg mice were both consistent with the increased PG levels and decreased VLDL secretion reported for the ob/ob CD36 Ϫ/Ϫ mice (10).…”

“…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 liver by promoting the formation and secretion of lipoprotein particles (10). It is conceivable that an in vivo model in which CD36 expression can be temporally and liver-specifically regulated will help to establish the function of CD36 in hepatic lipid metabolism and help to explain the discrepancies arising from earlier studies.…”

Structure-Function of CD36 and Importance of Fatty Acid Signal Transduction in Fat Metabolism

“…These include the role of CD36 in fat perception (22, 70), phospholipid remodeling and eicosanoid production (43), chylomicron production (93), release of intestinal peptides (90) during fat absorption, secretion of hepatic VLDL (66) and adaptation of myocardial rhythm to energy deprivation (73) as highlighted below.…”

The Role of Fatty Acid Metabolism and Apolipoproteins in Ths-Induced Hepatic Steatosis in Mice

“…A decrease in VLDL assembly and secretion has been associated with hepatic steatosis [14][15][16]. VLDL particles, which are synthesized in the liver, are responsible for delivering TGs to the different cells of the body.…”