VCAM-1: closing the gap between lipotoxicity and endothelial dysfunction in nonalcoholic steatohepatitis

Abstract

Nonalcoholic fatty liver disease (NAFLD) results in the accumulation of fat in the liver and can progress as an inflammatory disorder with considerable vascular endothelial dysfunction known as nonalcoholic steatohepatitis (NASH). Inflammatory signals can trigger the expression of vascular cell adhesion molecule 1 (VCAM-1) on endothelial cells. VCAM-1 is a surface protein that induces adherence and extravasation of monocytes to blood vessels. In this issue of the JCI, Furuta et al. report on their sequencing of RNA transcripts from the livers of mice fed a NASH-inducing diet. VCAM-1 was upregulated in the whole liver as well as liver sinusoidal endothelial cells (LSECs). When the researchers incubated LSECs with palmitate, a toxic lipid, VCAM-1 was upregulated. Notably, inhibiting VCAM-1 in the NASH model reduced VCAM-1 expression, lessened infiltrating macrophages, and mitigated fibrosis. This study connects steatosis to endothelial dysfunction and inflammation and suggests that targeting VCAM-1 may address fibrosis in patients with NASH.

Figure 1. Model of hepatic macrophage infiltrate and fibrosis.

Following distortion and injury of LSECs by steatotic hepatocytes, macrophages infiltrate and adhere to the sinusoidal lining via VCAM-1. The persistence of this cascade likely results in progressive steatohepatitis and fibrosis. Ameliorating the precipitating endothelial cell dysfunction (possibly through VCAM-1) may remedy NASH-related fibrosis.