CD36 in liver diseases

Abstract

Cluster of differentiation 36 (CD36) is a transmembrane glycoprotein with the ability to bind to multiple ligands and perform diverse functions. Through the recognition of long-chain fatty acids, proteins containing thrombospondin structural homology repeat domains such as thrombospondin-1, and molecules with molecular structures consistent with danger- or pathogen-associated molecular patterns, CD36 participates in various physiological and pathological processes of the body. CD36 is widely expressed in various cell types, including hepatocytes and KCs in the liver, where it plays a pivotal role in lipid metabolism, inflammation, and oxidative stress. Accumulating evidence suggests that CD36 plays a complex role in the development of nonalcoholic simple fatty liver disease and NASH and contributes to the pathogenesis of inflammatory liver injury, hepatitis B/hepatitis C, liver fibrosis, and liver cancer. This review summarizes the current understanding of the structural properties, expression patterns, and functional mechanisms of CD36 in the context of liver pathophysiology. Furthermore, the potential of CD36 as a therapeutic target for the prevention and treatment of liver diseases is highlighted.

Graphical abstract

FIGURE 1

CD36 serves as both a signal transducer and a fatty acid transporter. Binding of CD36 to TSR domain proteins, including TSP-1 and -2, activates phosphorylation of Fyn, and subsequently activates p38 and caspase, inducing apoptosis and antiangiogenesis in vascular endothelial cells. TSP-1 interactions with CD36 can also recruit the phosphatase SHP1 to VEGFR2 in endothelial cells, and thereby inhibit VEGF-induced angiogenesis. In response to extracellular signals such as DAMPs and PAMPs, CD36 assembles and interacts with other membrane receptors, including NKA, TLRs, integrins, and tetraspanins, forming different signaling complexes; the signaling complex triggers an intracellular signaling cascade that starts with SFK activation and then signals downstream effectors including MAPK, AMPK, and Vav. Activation of these effectors leads to ROS production and NF-κB pathway activation, which results in proinflammatory responses. Meanwhile, CD36 could bind to LCFAs and facilitate their transmembrane transport, which impacts fatty acid metabolism and may contribute to the activation of the PPARs pathway. Created with Biorender.com. Abbreviations: AMPK, adenosine 5′monophosphate-activated protein kinase; CD36, cluster of differentiation 36; DAMP, danger-associated molecular pattern; LCFA, long-chain fatty acid; MAPK, mitogen-activated protein kinase; NKA, neurokinin A; PAMP, pathogen-associated molecular pattern; PPAR, peroxisome proliferator–activated receptor; ROS, reactive oxygen species; SFK, src-family kinase; TLR, Toll-like receptor; TSR, thrombospondin structural homology repeat.

FIGURE 2

CD36-mediated excessive uptake of fatty acids contributes to NASH. CD36 increases FFA uptake in the liver, and excessive FFA influx could lead to peroxidation and oxidative stress in hepatocytes, causing lipid disorders. Lipid disorders, in turn, induce lipotoxicity, cytotoxicity, mitochondrial autophagy, and apoptosis in hepatocytes, promoting tissue damage and inflammation, which drives hepatosteatosis onset and might contribute to its progression to NASH. Created with Biorender.com. Abbreviations: CD36, cluster of differentiation 36; FFA, free fatty acid.