A novel role of RNase L in the development of nonalcoholic steatohepatitis

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and affects about 25% of the population globally. NAFLD has the potential to cause significant liver damage in many patients because it can progress to nonalcoholic steatohepatitis (NASH) and cirrhosis, which substantially increases disease morbidity and mortality. Despite the key role of innate immunity in the disease progression, the underlying molecular and pathogenic mechanisms remain to be elucidated. RNase L is a key enzyme in interferon action against viral infection and displays pleiotropic biological functions such as control of cell proliferation, apoptosis, and autophagy. Recent studies have demonstrated that RNase L is involved in innate immunity. In this study, we revealed that RNase L contributed to the development of NAFLD, which further progressed to NASH in a time‐dependent fashion after RNase L wild‐type (WT) and knockout mice were fed with a high‐fat and high‐cholesterol diet. RNase L WT mice showed significantly more severe NASH, evidenced by widespread macro‐vesicular steatosis, hepatocyte ballooning degeneration, inflammation, and fibrosis, although physiological and biochemical data indicated that both types of mice developed obesity, hyperglycemia, hypercholesterolemia, dysfunction of the liver, and systemic inflammation at different extents. Further investigation demonstrated that RNase L was responsible for the expression of some key genes in lipid metabolism, inflammation, and fibrosis signaling. Taken together, our results suggest that a novel therapeutic intervention for NAFLD may be developed based on regulating the expression and activity of RNase L.

Serum RNase L levels in patients with chronic hepatitis B virus infection

“…On the other hand, degradation of proteins, such as RNase L by diseased liver may be down, making serum RNase L elevated. Furthermore, a recent report utilizing RNase L knockout mice revealed that RNase L participates in steatosis, inflammation, and fibrosis in an animal model of nonalcoholic steatohepatitis 15 . This suggests that RNase L may play several roles in liver diseases independent of its antiviral activity.…”

“…and fibrosis in an animal model of nonalcoholic steatohepatitis. 15 This suggests that RNase L may play several roles in liver diseases independent of its antiviral activity. These mechanisms are not mutually exclusive.…”