Metabolic insults-initialised nonalcoholic steatohepatitis promoted by fine particulate matter challenge: A mechanism involving RNF15-driven ASK1 degradation

Epidemiological studies have found that long-term fine particulate matter (PM_2.5) exposure is closely linked to the incidence of nonalcoholic steatohepatitis (NASH). However, no approved clinical medication or effective treatment strategy is available because its complex pathological processes are poorly understood. RING-finger-protein 15 (RNF15) is an E3 ubiquitin-protein ligase that abounds in the liver. We investigated whether and by what mechanisms RNF15 influences hepatic metabolic homeostasis to mitigate steatohepatitis. RNF15 expression was confirmed in human patients with NASH and rodent models. Here we identified RNF15 as a novel and efficient endogenic suppressor of apoptosis signal regulating kinase 1 (ASK1). Hepatocyte-specific Rnf15 ablation impairs liver energy homeostasis, is accompanied by glycometabolic disorder, synthetase of fatty acids, and an elevated inflammatory response, and remarkably promotes steatohepatitis progression. Conversely, lentivirus- or adeno-associated virus- and transgenic overexpression-induced Rnf15 gene therapy mitigates NASH in rodent models. Mechanistically, in response to metabolic stress, RNF15 binds to ASK1 and conjugates K48-linked ubiquitination to facilitate ASK1 degradation, which therefore prohibits hepatocyte ASK1 signalling and its downstream signalling cascade transduction. These findings reveal that the RNF15-ASK1 axis closely links PM_2.5 exposure, accelerated metabolic insults, initialised hepatic metabolic homeostasis, and steatosis, whose dysfunction promotes the steatohepatitis pathological process.