The deubiquitinating enzyme cylindromatosis mitigates nonalcoholic steatohepatitis

Abstract

Nonalcoholic steatohepatitis (NASH) is a common clinical condition that can lead to advanced liver diseases. Lack of effective pharmacotherapies for NASH is largely attributable to an incomplete understanding of its pathogenesis. The deubiquitinase cylindromatosis (CYLD) plays key roles in inflammation and cancer. Here we identified CYLD as a suppressor of NASH in mice and in monkeys. CYLD is progressively degraded upon interaction with the E3 ligase TRIM47 in proportion to NASH severity. We observed that overexpression of Cyld in hepatocytes concomitantly inhibits lipid accumulation, insulin resistance, inflammation and fibrosis in mice with NASH induced in an experimental setting. Mechanistically, CYLD interacts directly with the kinase TAK1 and removes its K63-linked polyubiquitin chain, which blocks downstream activation of the JNK-p38 cascades. Notably, reconstitution of hepatic CYLD expression effectively reverses disease progression in mice with dietary or genetically induced NASH and in high-fat diet-fed monkeys predisposed to metabolic syndrome. Collectively, our findings demonstrate that CYLD mitigates NASH severity and identify the CYLD-TAK1 axis as a promising therapeutic target for management of the disease.

Impact of neutralizing antibodies against AAV is a key consideration in gene transfer to nonhuman primates

“…However, the overall experimental design for the cited studies 1–4,9 in this correspondence challenges the conventional doctrine of previous findings on pre-existing NABs against AAV virus. For example, in the above studies in question, it was not stated whether any of the monkeys were screened for AAV8 NABs.…”

“…Recently, Hongliang Li and colleagues 1–4 published four studies in Nature Medicine applying AAV serotype 8 vectors (AAV8) in nonhuman primate (NHP) models of nonalcoholic steatohepatitis. In each study, genes delivered to the liver via AAV vectors demonstrated transduction in these large animal models, and therapeutic effects were achieved.…”

“…In an unpublished study, we found that 4% of 120 monkeys were seronegative for the AAV8 NAB (data not shown). It should also be noted that the probability of NAB occurrence should actually be higher in older animals, such as those used in these studies (aged 8–9 years) 1–4 , as they are more likely than younger animals to have been exposed to AAV8 and other AAV serotypes in their lifetime. Furthermore, in animals or humans lacking pre-existing NABs, the vector cannot be readministered (unless a different viral capsid is chosen) owing to potent NAB responses that occur within days after the initial exposure to vector, which can persist for months.…”

“…However, the high-titer NABs against AAV8 that should have developed from the first injection would have prevented any successful gene transduction by the second administration, particularly via an intravenous route 10,11 . A similar readministration experiment that did not consider the NAB issue was carried out in the CYLD study 4 . Also, we should note that even minor differences in NAB titers should result in wide interanimal variability, even in small animals.…”

Time to step‐up the fight against NAFLD

“…These MetS‐predisposed monkeys exhibit higher blood pressure and body weight than healthy controls. Importantly, moderate steatosis and inflammation developed in MetS‐predisposed monkeys fed a normal chow diet, and they also exhibit clear increases in the hepatic expression of profibrotic genes . When fed an HFD or even a simple high‐carbohydrate diet, MetS‐predisposed monkeys rapidly become obese and insulin resistant and develop hepatic inflammation with fibrosis .…”