Mice lacking cyclophilin B, but not cyclophilin A, are protected from the development of NASH in a diet and chemical-induced model

Abstract

Cyclophilins are a diverse family of peptidyl-prolyl isomerases (PPIases) of importance in a variety of essential cellular functions. We previously reported that the pan-cyclophilin inhibitor drug reconfilstat (CRV431) decreased disease in mice under the western-diet and carbon tetrachloride (CCl4) non-alcoholic steatohepatitis (NASH) model. CRV431 inhibits several cyclophilin isoforms, among which cyclophilin A (CypA) and B (CypB) are the most abundant. It is not known whether simultaneous inhibition of multiple cyclophilin family members is necessary for the observed therapeutic effects or if loss-of-function of one is sufficient. Identifying the responsible isoform(s) would enable future fine-tuning of drug treatments. Features of human liver fibrosis and complete NASH can be reliably replicated in mice by administration of intraperitoneal CCl4 alone or CCl4 in conjunction with high sugar, high cholesterol western diet, respectively. Here we show that while wild-type (WT) and Ppia-/- CypA KO mice develop severe NASH disease features under these models, Ppib-/- CypB KO mice do not, as measured by analysis of picrosirius red and hematoxylin & eosin-stained liver sections and TNFα immuno-stained liver sections. Cyclophilin inhibition is a promising and novel avenue of treatment for diet-induced NASH. In this study, mice without CypB, but not mice without CypA, were significantly protected from the development of the characteristic features of NASH. These data suggest that CypB is necessary for NASH disease progression. Further investigation is necessary to determine whether the specific role of CypB in the endoplasmic reticulum secretory pathway is of significance to its effect on NASH development.

Cyclophilin inhibition as a strategy for the treatment of human disease

“…The Gallay lab recently demonstrated that mice lacking CypB, unlike those lacking CypA, were protected from non-alcoholic steatohepatitis (NASH) in both dietary and chemically induced models. ( Stauffer et al, 2024 ). The resulting disruption of collagen folding and export, a central facilitation of liver fibrosis, is the predicted mechanism protecting mice from the development of NASH.…”

Cyclophilin D knockout significantly prevents HCC development in a streptozotocin-induced mouse model of diabetes-linked NASH

“…Cyclophilin A (PPIA, CypA) is a cytosolic enzyme which can be secreted and has been shown to play important roles in inflammation [26,27] and the lifecycle of multiple viruses such as HIV, HCV, and HBV [27][28][29][30]. Cyclophilin B (PPIB, CypB) localizes to the endoplasmic reticulum where it serves as a chaperone, aiding in the folding of nascent proteins such as collagen [31][32][33][34]. Cyclophilin D (PPIF, CypD) is a component of the mitochondrial permeability transition pore (mPTP) where it can influence pore sensitivity and mitochondrial permeability [35][36][37].…”