CD47-mediated regulation of glucose and lipid metabolism: implications for the pathogenesis of MASLD

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), has gradually become a leading cause of end-stage liver disease as a heterogeneous group of diseases. While the underlying mechanisms of MASLD remain incompletely understood, it is clear that glycolipid metabolism, coupled with subsequent disruptions in hepatic sinusoidal homeostasis and cellular senescence play significant roles in its onset and progression. In recent years, CD47 has been recognized not only as a critical target in cancer therapy but also as a participant in the development of metabolic diseases through complex signaling pathways. Increasing evidence suggests that CD47 is closely associated with the development of MASLD; however, its role in MASLD has not yet been widely explored. Therefore, this review aims to summarize current research on the potential role of CD47 in the pathogenesis of MASLD, particularly in relation to disturbances in glucose and lipid metabolism.

Keywords: CD47; MASLD; glucose metabolism; hepatic sinusoidal; lipid metabolism; mitochondrial; senescence.

Figure 1

CD47 regulation of glucose and lipid metabolism in MASLD. Insulin resistance (IR) is recognized as a critical factor in the development of metabolic dysfunction-associated steatotic liver disease (MASLD). In the presence of IR, fat accumulation and mitochondrial dysfunction are observed. Suppressing CD47 expression has the potential to improve both lipid and mitochondrial function via multiple mechanisms, thereby reducing hepatic lipid accumulation. Additionally, this inhibition may help mitigate insulin resistance and the cascade of metabolic disturbances associated with it. BAT, brown adipose tissue; WAT, white adipose tissue; FFA, free fatty acids; TG, triglycerides; DNL, de novo lipogenesis; VLDL, very-low-density lipoprotein; Cdc42, cell division cycle 42; GDP, guanosine diphosphate; GTP, guanosine triphosphate; cGMP, cyclic guanosine monophosphate; AMP, cyclic adenosine mono-phosphate; PKG, protein kinase G; VEGF-A, vascular endothelial growth factor-A; VEGF-B, vascular endothelial growth factor-B; CPT1b, carnitine palmitoyl l transferase 1B; UCP1, Uncoupling protein 1;PGC-α, PGC-1 alpha; Drp1, Dynamin-related protein 1; Nrg4, neuregulin 4; Image created using the www.biorender.com.

Figure 2

The role of CD47 in regulating hepatic sinusoidal function and cellular senescence. (1) liver sinusoidal endothelial cells (LSECs) play a pivotal role in maintaining sinusoidal homeostasis, supporting the normal function of hepatic stellate cells (HSCs) and macrophages. Under physiological conditions, LSECs exhibit anti-inflammatory and anti-fibrotic properties. However, phenotypic alterations in LSECs can lead to HSC activation and exacerbate macrophage infiltration. The maintenance of LSEC phenotype stability is dependent on nitric oxide (NO). The binding of TSP1 to CD47 inhibits vascular endothelial growth factor receptor 2 (VEGFR2) activation and its downstream signaling, reducing NO production. This, in turn, induces LSEC defenestration through myosin activation via the Rho-ROCK pathway. Additionally, studies suggest that targeting CD47 can modulate macrophage and HSC function via pathways such as Signal regulatory protein alpha (SIRPα) and YAP/TEAD4, thereby reducing hepatic inflammatory infiltration and fibrosis. (2) Aging contributes to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) through various mechanisms, including its effects on hepatic glycolipid metabolism, mitochondrial function, and intrahepatic cellular processes. The interaction between TSP1 and CD47 influences the pRb-E2F1 and p53 pathways, thereby regulating the cell cycle. Nuclear factor-κB (NF-κB), a central regulator of inflammatory responses, is also modulated by CD47, with CD47 levels positively correlated with NF-κB expression. LSEC, liver sinusoidal endothelial cell;TSP1, thrombospondin-1; eNOS, endothelial nitric oxide synthase;NO, nitric oxide;cGMP, cyclic guanosine monophosphate;Rho, Ras homolog (GTPase);Rock, Rho-associated, coiled-coil-containing protein kinase;CCL2, C-C motif chemokine ligand 2;TNFα, tumor necrosis factor alpha;IL-1, interleukin-1;IL6, interleukin-6;NF-κB, nuclear factor-κB;PPARα, peroxisome proliferator-activated receptor alpha;HSC, hepatic stellate cell;TGFβ, transforming growth factor beta;MIP-2, macrophage inflammatory protein 2;MCP-1, monocyte chemoattractant protein 1;CCL3, C-C motif chemokine ligand 3;YAP1, Yes-associated protein 1;TEAD1, TEA domain transcription factor 1;Col1a1, collagen I chain;α-SMA, alpha-smooth muscle actin;SIRPα, signal regulatory protein alpha; ECM, extracellular matrix; CDK4, cyclin-dependent kinase 4; CDK6, cyclin-dependent kinase 6; E2F1, E2F transcription factor 1; pRb, phosphorylated Rb; NOX-1, NADPH oxidase 1; p53, tumor protein p53; Image created using the www.biorender.com.