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

Abstract

Affecting more than 30% of the Western population, nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications, including nonalcoholic 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 NAFLD progression. We evaluated the consequences of EDP accumulation in mice and of elastin receptor complex (ERC) activation on lipid storage in hepatocytes, inflammation, and fibrosis development. The accumulation of EDPs induces hepatic lipogenesis (i.e., SREBP1c and ACC), inflammation (i.e., Kupffer cells, IL-1β, and TGF-β), and fibrosis (collagen and elastin expression). These effects are induced by inhibition of the LKB1-AMPK pathway by ERC activation. In addition, pharmacological inhibitors of EDPs demonstrate that this EDP-driven lipogenesis and fibrosis relies on 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.

Short-term strength training reduces gluconeogenesis and NAFLD in obese mice

“…Finally, subjects with hepatic steatosis treated with MK-4074 (liver-specific inhibitor of ACC1 and ACC2) had a 36% reduction in lipid content after 4 weeks of intervention (Kim et al 2017). Thus, therapies that reduced the content levels activity of ACC in the liver were the subject of several studies for the prevention and treatment of NAFLD (Nuñez-Durán et al 2018, Romier et al 2018. In this context, aerobic training is known to provide an increase in the phosphorylation of ACC in the liver of obese animals, inhibiting its lipogenic action (Rector et al 2008).…”

Recent Advances in Elastin-Based Biomaterials

“…CD36 receptor is also modulated by Neu-1, which activates an intracellular signaling cascade that increases the uptake of oxLDL by macrophages, thus, contributing to atherosclerotic plaque formation (50). EDPs have been shown as regulators of insulin resistance development (51), chemotactic attractors to cancer cells (52), and contributors to lipid accumulation in hepatocytes in patients with nonalcoholic steatohepatitis (NASH) (53). It has been demonstrated that, besides physiological aging, several genetic alterations also lead to connective tissue disorders related to elastin degradation.…”

Overview of the Pathogenesis, Genetic, and Non-Invasive Clinical, Biochemical, and Scoring Methods in the Assessment of NAFLD

“…The first model was composed of six proteins (fibrinogen β chain, retinol binding protein 4, serum amyloid P component, lumican, transgelin 2, and CD5 antigen-like), and the second involved three proteins (component C7, insulin-like growth factor acid labile subunit, and transgelin 2); the AUROC values ranged from 0.83–0.91 for different stages of NAFLD [158]. Due to multiomic studies, numerous biomarkers have been revealed to be associated with NAFLD, as they are involved in necroinflammation and fibrogenesis [159,160,161,162,163,164,165].…”