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.

1. Introduction

Liver disease is a worldwide health care concern, contributing to more than two million deaths annually and accounting for 4% of all deaths worldwide [1]. At present, nonalcoholic fatty liver disease (NAFLD) is the predominant etiology of chronic hepatitis in Western societies, with its prevalence rapidly increasing on a global scale [2]. Notably, this condition impacts a quarter of the global adult population. Over the past two decades, with rapid lifestyle changes, NAFLD has become the most common liver disease in China. The prevalence of NAFLD has increased from 23.8% to 29.0%; however, NAFLD has not received sufficient attention [3]. Over the past 30 years, the total number of deaths among NAFLD patients worldwide has doubled. The overall percentage of deaths attributed to NAFLD-related causes has increased from 0.10% to 0.17% [1]. Owing to continued high rates of adult obesity and type 2 diabetes mellitus, coupled with an aging population, the total NAFLD population is forecasted to increase by 18.3% in the U.S., whereas the prevalence of nonalcoholic steatohepatitis (NASH) cases is expected to increase by 56% by 2030 [4,5]. Currently, NAFL is defined as a catch-all term that encompasses a variety of disorders characterized by steatosis affecting a minimum of 5% of hepatocytes, combined with metabolic risk factors (such as type 2 diabetes and obesity). This definition excludes heavy alcohol usage-induced hepatitis or other chronic liver diseases. Furthermore, NASH is characterized by hepatic damage, including hepatocyte ballooning degeneration, diffuse lobular inflammation, and fibrosis [6]. Up to 15% of individuals with NAFLD progress to NASH, the more severe form of the disease. Whereas simple steatosis is often considered a “benign” condition, individuals with NASH face the potential for progression to fibrosis, cirrhosis and hepatocellular carcinoma (HCC) and have an elevated risk of liver-related mortality. In addition, HCC may develop in individuals with NAFLD without cirrhosis, termed NAFLD-HCC [7].

Integrins are α/β heterodimeric cell adhesion molecules, mediating cell-cell, cell-extracellular matrix (ECM) and cell-pathogen interactions and transmit signals bidirectionally across the plasma membrane [8]. In vertebrates, 18 α subunits and 8 β subunits exist, which combine into 24 types of integrins that are broadly distributed across numerous organs and tissues (Figure 1). Integrins, as type I transmembrane proteins, control cell-cell and cell-ECM adhesion, thereby impacting a variety of cellular functions, including migration, proliferation, wound repair, and other cellular activities [9]. In NAFLD, integrins serve as the primary mechanism by which cells in the liver sense their extracellular environment, such as accumulated lipids that trigger the “first hit” in NAFLD, which involves insulin resistance (IR) and hepatic steatosis [10]. Liver tissue eventually undergoes lipid peroxidation, endoplasmic reticulum (ER) stress, oxidative stress, inflammatory damage, and other pathological alterations, contributing to the development of the “multiple-hit” scenario [11]. During NAFLD-induced fibrogenesis, integrins mediate diverse cell-matrix and cell-cell interactions. In NASH-related HCC, which progresses annually [12], integrins are typically dysregulated and are involved in nearly every stage of cancer progression, including epithelial-mesenchymal transition (EMT), angiogenesis, cell proliferation, adhesion, and invasion [13]. Moreover, integrins are considered to influence multiple components within the tumor microenvironment of HCC, such as lymphocyte activation, migration, and extravasation.