Endothelial Cell Dysfunction and Nonalcoholic Fatty Liver Disease (NAFLD): A Concise Review

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. It is strongly associated with obesity, type 2 diabetes (T2DM), and other metabolic syndrome features. Reflecting the underlying pathogenesis and the cardiometabolic disorders associated with NAFLD, the term metabolic (dysfunction)-associated fatty liver disease (MAFLD) has recently been proposed. Indeed, over the past few years, growing evidence supports a strong correlation between NAFLD and increased cardiovascular disease (CVD) risk, independent of the presence of diabetes, hypertension, and obesity. This implies that NAFLD may also be directly involved in the pathogenesis of CVD. Notably, liver sinusoidal endothelial cell (LSEC) dysfunction appears to be implicated in the progression of NAFLD via numerous mechanisms, including the regulation of the inflammatory process, hepatic stellate activation, augmented vascular resistance, and the distortion of microcirculation, resulting in the progression of NAFLD. Vice versa, the liver secretes inflammatory molecules that are considered pro-atherogenic and may contribute to vascular endothelial dysfunction, resulting in atherosclerosis and CVD. In this review, we provide current evidence supporting the role of endothelial cell dysfunction in the pathogenesis of NAFLD and NAFLD-associated atherosclerosis. Endothelial cells could thus represent a "golden target" for the development of new treatment strategies for NAFLD and its comorbid CVD.

Keywords: CVD; LSECs; NAFLD; endothelial dysfunction; inflammation; sinusoidal endothelial cells; vascular endothelial cells.

Figure 1

The role of endothelial cells in NAFLD pathogenesis and the interplay between CVD and NAFLD. LSECs are located at the interface between the blood stream and the liver parenchyma. LSECs regulate blood flow in response to shear stress, mainly through increased NO synthesis and bioavailability as well as through ET-1 reduction, which are both mediated by KLF2. LSECs also regulate the activation of KCs and HSCs during NASH progression. The expression of SRs, MR, and FcγRIIb2 endows LSECs with high endocytic capacity; of note, the reduced endocytic capacity of LSECs precedes fibrosis in NAFLD. The increased expression of adhesion molecules during the early stage of NAFLD enhances the recruitment of monocytes to the inflamed endothelium, leading to the activation of an inflammatory response in NASH. Impaired autophagy has been associated with the development of steatosis and fibrosis through—among others—the upregulation of adhesion molecules and pro-inflammatory mediators during the progression of the disease. Moreover, hepatocyte-derived EVs contribute to the formation of inflammatory foci by the recruitment of macrophages into the hepatic sinusoids. Both HSC- and LSEC-derived EVs play crucial roles in the maintenance of the balance between extracellular matrix production and degradation and the consequent progression towards the regeneration of hepatic cells or fibrosis. The anti-inflammatory features of LSECs observed during the early stage of NAFLD development are attributable—among others—to decreased CCL and CXCL expression through MAPK signaling activation and increased secretion of IL-10 by Th1 cells. NAFLD is strongly related to vascular endothelial dysfunction and consequence atherosclerosis. The overexpression of inflammatory mediators, elevated insulin resistance, and oxidative stress are key players in this interrelation. Increased levels of inflammatory molecules such as circulating fetuin-A, ADMA, cRP, and SeP have been associated with an elevated risk of CVDs in NAFLD patients and vice versa: the low-grade inflammatory milieu of atherosclerosis could promote the progression of NAFLD.

Figure 2

The LSECs’ anti-inflammatory and pro-inflammatory profiles during the progression of NAFLDAt the early stage of NAFLD, LSECs display an anti-inflammatory function characterized by a reduced expression of chemokines such as CCL2, CXCL10, and CXCL16 through MAPK signaling and an induced expression of IL-10 by Th1 cells through the activation of Notch signaling. The activation of Notch signaling manifests anti-inflammatory effects through the induction of eNOS/sGC levels.During the progression of NAFLD from simple steatosis to NASH and cirrhosis, LSECs exhibit a pro-inflammatory phenotype mediated mostly through the activation of the NF-kB pathway. NF-kB regulates the expression of adhesion molecules (VCAM-1, ICAM-1, E-selectin, and VAP-1) as well as the secretion of pro-inflammatory cytokines (TNF-α, IL-1, and IL-6). The secretion of inflammatory mediators is also regulated by TLRs and NO bioavailability. Elevated expression of adhesion molecules leads to induced leukocyte recruitment and their translocation into the hepatic parenchyma. On the other hand, increased expression of inflammatory mediators along with LSEC dysfunction stimulates the activation of KCs and leukocyte chemoattraction. The impaired LSEC autophagy observed during the progression of NAFLD also leads to the upregulation of adhesion molecule and chemokine expression, enhancing the inflammatory response. Reduced eNOS and increased iNOS contribute to the development of inflammation, the activation of KCs, and the recruitment of bone-marrow-derived macrophages. Abbreviations: ICAM-1: Intercellular adhesion molecule-1; IL-1: Interleukin 1; IL-6: Interleukin 6; LSECs: Liver sinusoidal endothelial cells; MCP1: Monocyte chemoattractant protein-1; NF-kB: Nuclear factor kappa B; NO: nitric oxide; TNFa: Tumor necrosis factor alpha; VAP-1: Vascular adhesion protein1; VCAM-1: Vascular cell adhesion molecule-1; BMMs: bone-marrow-derived macrophages; TLR: Toll-like receptor; CXCL12: C-X-C motif chemokine ligand 12; CXCR4: C-X-C chemokine receptor type 4; KC: Kupffer cells. This image was derived from the free medical site http://smart.servier.com/ (accessed on 1 July 2022) by Servier, licensed under a Creative Commons Attribution 3.0 Unported license.