Production of Elastin-Derived Peptides Contributes to the Development of Nonalcoholic Steatohepatitis

Abstract

Affecting more than 30% of the western population, non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications including non-alcoholic steatohepatitis (NASH), cancer, hypertension and atherosclerosis. Insulin resistance and obesity are described as potential causes of NAFLD. However, we surmised that factors such as extracellular matrix remodeling of large blood vessels, skin or lungs may also participate in the progression of liver diseases. We studied the effects of elastin-derived peptides (EDPs), biomarkers of aging, on the NAFLD progression. We evaluated the consequences of EDP accumulation in mice and of elastin receptor complex activation (ERC) on the lipid storage in hepatocytes, inflammation, and fibrosis development. The accumulation of EDPs induces hepatic lipogenesis (i.e. SREBP-1C, ACC), inflammation (i.e. Kupffer cells, IL-1β, TGFβ) and fibrosis (collagen and elastin expression). Those effects are induced by the inhibition of LKB1-AMPK pathway by ERC activation. In addition, pharmacological inhibitors of EDPs demonstrate that this EDP-driven lipogenesis and fibrosis relies on the engagement of the ERC. Our data reveal a major role of EDPs in the development of NASH, and they provide new clues for understanding the relationship between NAFLD and vascular aging.