Integrins and NAFLD-associated liver diseases: clinical associations, pathophysiological mechanisms and pharmacological implications

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and poses a substantial health burden with increasing incidence globally. NAFLD encompasses a spectrum extending from hepatic steatosis to nonalcoholic steatohepatitis (NASH), with the possibility of progressing to cirrhosis or, in severe instances, hepatocellular carcinoma (HCC). NAFLD extends beyond simple metabolic disruption and involves multiple immune cell-mediated inflammatory processes. Integrins are a family of heterodimeric transmembrane cell adhesion receptors that regulate various aspects of NAFLD onset and progression, including hepatocellular steatosis, hepatic stellate cell (HSC) activation and immune cell infiltration. In this review, we comprehensively summarize the involvement of integrins in NAFLD, as well as the downstream signal transduction mediated by these receptors. Furthermore, we present the latest clinical and preclinical findings on drugs that target integrins for steatosis, inflammation, fibrosis and NAFLD-related HCC treatment.

Keywords: NAFLD; NAFLD-related HCC; NASH; diagnostics and treatments; integrins.

Figure 1

Integrin family and classification Twenty four integrins consist of 18 α subunits and 8 β subunits, which can be classified into RGD-binding integrins, leukocyte cell-adhesion integrins, collagen-binding integrins, and laminin-binding integrins.

Figure 2

Representation of the structure of the integrin α and β subunits Integrins are composed of α and β subunits, forming heterodimeric transmembrane glycoproteins. The α-chain consists of four or five extracellular domains: a seven-bladed β-propeller, a thigh, and two calf domains. Nine of the 18 integrin α chains contain an αI domain. The β subunit comprises seven domains with flexible and complex interconnections. The red and blue asterisks denote Ca2+- and Mg2+-binding sites, respectively. The hollow asterisk denotes the Ca2+-binding site in the fourth repeat of the β-propeller domain in certain α subunits.

Figure 3

Activation and signaling of integrins Integrins can adopt at least three distinct conformational states, each with varying affinities for ligands: the low-affinity “bent” conformation, the intermediate-affinity “extended conformation with closed headpiece”, and the high-affinity “extended conformation with open headpiece”. Integrins mediate cell signaling transduction through two mechanisms, known as “inside-out” signaling and “outside-in” signaling. In the “inside-out” signaling pathway, intracellular signals induce conformational changes in integrins, altering their ligand-binding affinity. Conversely, in the “outside-in” signaling pathway, engagement with extracellular ligands triggers conformational changes in integrins, transmitting signals into the cell and initiating downstream signaling cascades.

Figure 4

Roles of integrins in hepatocyte functions in NAFLD Hepatic integrin α1β1 induces the phosphorylation and subsequent activation of IRS1 and AKT, promoting liver insulin action and preventing diet-induced liver insulin resistance. Integrin α5β1 activates of NLRP3 inflammasome and pyroptosis in hepatocytes during NAFLD.

Figure 5

The role of integrins in liver fibrosis in NASH Recruited αM+ macrophages, αX+ macrophages, α4β7+ T cells are accumulated in NASH liver, which induce liver inflammation and fibrosis. αE+ cDC1 and β7+ TH17 are employed to reduce metabolic disorders and steatosis in obese mice. Activated integrin α9β1 is endocytosed by hepatocytes and secreted in the form of extracellular vesicles (EVs), which are further captured by monocytes. Captured integrin α9β1 mediates monocyte adhesion to LSECs by binding to VCAM-1, which accelerates liver fibrosis. αV integrins are the regulators of fibrosis in HSCs and LSECs, making them therapeutic targets in NASH. Additionally, integrin α8β1 promotes liver fibrosis by activating TGF-β in HSCs.