Proteasome dysfunction under compromised redox metabolism dictates liver injury in NASH through ASK1/PPARγ binodal complementary modules

Abstract

Incidence of hepatotoxicity following acute drug-induced proteasomal inhibition and development of chronic proteasome dysfunction in obesity and insulin resistance underscores the crucial importance of hepatic protein homeostasis albeit with an elusive molecular basis and therapeutic opportunities. Apart from lipotoxicity and endoplasmic reticulum (ER) stress, herein we report that hepatocytes are highly susceptible to proteasome-associated metabolic stress attune to altered redox homeostasis. Bortezomib-induced proteasomal inhibition caused severe hepatocellular injury independent of ER stress via proapoptotic Apoptosis Signal-regulating Kinase 1 (ASK1)- c-Jun N-terminal kinase (JNK1)- p38 signaling concomitant with inadequate peroxisome proliferator-activated receptor γ (PPARγ)- Nuclear factor erythroid 2-related factor 2 (Nrf2) -driven antioxidant response. Although inhibition of ASK1 rescued acute hepatotoxicity, hepatic depletion of PPARγ or its physiological activator pigment epithelium-derived factor (PEDF) further aggravated liver injury even under ASK1 inhibition, emphasizing that endogenous PPARγ driven antioxidant activity serves as a prerequisite for the favorable therapeutic outcome of ASK1 inhibition. Consequently, ASK1 inhibitor selonsertib and PPARγ agonist pioglitazone in pharmacological synergism ameliorated bortezomib-induced hepatotoxicity and significantly prolonged survival duration in mice. Moreover, we showed that proteasome dysfunction is associated with ASK1 activation and insufficient PPARγ/Nrf2-driven antioxidative response in a subset of human nonalcoholic steatohepatitis (NASH) patients and the preclinical NASH model. The latter remains highly responsive to the drug combination marked by revamped proteasomal activity and alleviated hallmarks of NASH such as steatosis, fibrosis, and hepatocellular death. We thus uncovered a pharmacologically amenable interdependent binodal molecular circuit underlying hepatic proteasomal dysfunction and associated oxidative injury.

Oxidative Stress in Non-Alcoholic Fatty Liver Disease

“…A further study reported that the dysfunction of redox homeostasis induces hepatocytes to be highly susceptible to proteasome-associated metabolic stress. In comparison, insufficient peroxisome proliferator activating ligand receptors (PPAR) γ/Nrf2-driven antioxidative response is the main factor [134]. Moreover, the interaction between NF-κB and Nrf2 is also a noticeable target for NAFLD progression.…”

DUSP9 alleviates hepatic ischemia/reperfusion injury by restraining both mitogen-activated protein kinase and IKK in an apoptosis signal-regulating kinase 1-dependent manner

“…Another limitation of the present study is the lack of real-world clinical analysis. As a regulator of TRAF6/IKK in addition to MAPK [42] , the efficacy of ASK1 drugs against NAFLD is still unclear in some clinical studies [ 43 , 44 ] . The results of clinical studies on ASK1 inhibitors in NAFLD are gradually emerging, but their clinical application in liver I/R injury is relatively inadequate with regard to their target diversity.…”

Nonalcoholic steatohepatitis and mechanisms by which it is ameliorated by activation of the CNC-bZIP transcription factor Nrf2

“…In human studies, there are older data suggesting that Nrf2 may be activated in livers of NASH patients, though this must be considered with the caveat that there is uncertainty about the validity of matched 'normal' human liver specimens used as the reference [371,372]. More recent comparisons using Principal Component Analysis of gene expression data sets from livers of NASH patients with those from livers deemed to be healthy has revealed that Nrf2-target gene expression is significantly diminished in humans exhibiting NASH [373].…”