From fat to FAT (CD36/SR-B2): Understanding the regulation of cellular fatty acid uptake

Abstract

The molecular mechanisms underlying the cellular uptake of long-chain fatty acids and the regulation of this process have been elucidated in appreciable detail in the last decades. Two main players in this field, each discovered in the early 1990s, are (i) a membrane-associated protein first identified in adipose ('fat') tissue and referred to as putative fatty acid translocase (FAT)/CD36 (now officially designated as SR-B2) which facilitates the transport of fatty acids across the plasma membrane, and (ii) the family of transcription factors designated peroxisome proliferator-activated receptors (PPARα, PPARγ, and PPARβ/δ) for which fatty acids and fatty acid metabolites are the preferred ligand. CD36/SR-B2 is the predominant membrane protein involved in fatty acid uptake into intestinal enterocytes, adipocytes and cardiac and skeletal myocytes. The rate of cellular fatty acid uptake is regulated by the subcellular vesicular recycling of CD36/SR-B2 from endosomes to the plasma membrane. Fatty acid-induced activation of PPARs results in the upregulation of the expression of genes encoding various proteins and enzymes involved in cellular fatty acid utilization. Both CD36/SR-B2 and the PPARs have been implicated in the derangements in fatty acid and lipid metabolism occurring with the development of pathophysiological conditions, such as high fat diet-induced insulin resistance and diabetic cardiomyopathy, and have been suggested as targets for metabolic intervention. In this brief review we discuss the discovery and current understanding of both CD36/SR-B2 and the PPARs in metabolic homeostasis.

LCFA Uptake and FAT/CD36: molecular cloning, tissue expression and mRNA expression responses to dietary oil sources in grass carp (Ctenopharyngodon idellus)

“…In this sense, the intracellular transport of free FAs in mammals is facilitated by specific low-molecularweight and highly conserved cytoplasmic proteins that bind both long-chain FAs and other hydrophobic ligands. These fatty acid binding proteins (FABPs) are tissue specific and those from the liver, intestine, adipose tissue, brain and heart have been characterized extensively in mammals (Glatz and Luiken 2017). Similar studies have been reported in different fish species (Tocher 2003).…”

“…(Jump 2004; reviewed by Glatz and Luiken 2017). Initially, it was considered that LCFAs were taken up by cells through passive diffusion mechanisms (Kamp et al 2003;Pownall and Hamilton 2003;Hamilton and Brunaldi 2007), while evidence has shown that LCFA uptake is also facilitated by a proteinmediated mechanism Bonen et al 2007;Guo et al 2013).…”

“…FAT/CD36-mediated FA transport into the skeletal muscle was reported to be critically coupled with muscle fuel selection and FA oxidation (McFarlan et al 2012;Kim and Lim 2016), probably indicating that an increase in FAT/CD36 stimulated fat lipolysis and oxidation . In mammals, FAT/CD36 (SR-B2) has been described to be implicated in lipid and FA disorders such as in the aetiology of obesity-induced or high fat diet-induced ectopic lipid accumulation and insulin resistance (Glatz et al 2010;Liu et al 2016;Glatz and Luiken 2017).…”

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate‐induced apoptosis

“…We recently showed that the vast majority of carbons contributing to the intracellular lipid pool in BrCa cells arise from extracellular FAs and not from glucose or glutamine (Balaban et al ., 2017). Cells take up FAs from the bloodstream or local microenvironment via various surface transport proteins (Glatz and Luiken, 2017). FAs are then condensed into and stored as TAG in lipid droplets (Farese and Walther, 2009) and other complex lipids including phospholipids (Louie et al ., 2013), or enter the mitochondria for β‐oxidation (Bruce et al ., 2009).…”

Lipid transfer proteins in the assembly of apoB-containing lipoproteins

“…Fatty acids, glycerol, and monoacylglycerols are important precursors for their synthesis and are obtained from two sources. First, these precursors are taken up by cells from the extracellular environment via transporters present on the plasma membrane, such as CD36 and fatty acid transport proteins (10; [19][20][21], and are carried by cytoplasmic proteins, e.g., fatty acid-binding proteins (10;22), from the plasma membrane to the ER. Second, these precursors can be generated intracellularly after the hydrolysis of lipids stored in cytoplasmic lipid droplets (cLDs).…”