Double Knockout of Peroxiredoxin 4 (Prdx4) and Superoxide Dismutase 1 (Sod1) in Mice Results in Severe Liver Failure

Abstract

Mice that are deficient in superoxide dismutase 1 (Sod1), an antioxidative enzyme, are susceptible to developing liver steatosis. Peroxiredoxin 4 (Prdx4) catalyzes disulfide bond formation in proteins via the action of hydrogen peroxide and hence decreases oxidative stress and supports oxidative protein folding for the secretion of lipoproteins. Because elevated reactive oxygen species induce endoplasmic reticulum stress, this negative chain reaction is likely involved in the development of nonalcoholic fatty liver diseases and more advanced steatohepatitis (NASH). In the current study, we generated Prdx4 and Sod1 double knockout (DKO; Prdx4−/ySod1−/−) mice and examined whether the combined deletion of Prdx4 and Sod1 aggravated liver pathology compared to single knockout and wild-type mice. The secretion of triglyceride-rich lipoprotein was strikingly impaired in the DKO mice, leading to aggravated liver steatosis. Simultaneously, the activation of caspase-3 in the liver was observed. The hyperoxidation of Prdxs, a hallmark of oxidative stress, occurred in different isoforms that are uniquely associated with Sod1−/− and Prdx4−/y mice, and the effect was additive in DKO mouse livers. Because DKO mice spontaneously develop severe liver failure at a relatively young stage, they have the potential for use as a model for hepatic disorders and for testing other potential treatments.

Mutual interaction between oxidative stress and endoplasmic reticulum stress in the pathogenesis of diseases specifically focusing on non-alcoholic fatty liver disease

“…Stimulation of lipogenesis and the inhibition of lipoprotein secretion would cooperatively elevate lipid droplet accumulation, which would consequently result in the development of liver steatosis (Figure 3 ). This interdependent work of dealing with oxidative stress and ER stress in liver steatosis is further supported by recent observations showing the double knockout of SOD1 and PRDX4 result in aggravated liver damage compared to singly knockout mice[ 144 ].…”

miR‐139‐5p upregulation alleviated spontaneous recurrent epileptiform discharge‐induced oxidative stress and apoptosis in rat hippocampal neurons via regulating the Notch pathway

“…MDA is a lipid peroxidation by‐product and an indicator of cellular oxidation status indicator, and its accumulation was found evidently increased in multiple neurological diseases, such as epilepsy (Cheng et al, 2011; Deepa et al, 2008). SOD has been found to scavenge superoxide radicals and play a protective role against oxidative stress; ROS could induce neuronal death and thereby produce a detrimental effect on the brain, especially the hippocampus, and removal of ROS was found to prevent oxidative stress and HN loss (Homma et al, 2018; Pearson et al, 2015). Oxidative stress and mitochondrial dysfunction resulting from seizures also emerged as key factors that led to epileptogenesis (Waldbaum & Patel, 2010).…”

Atorvastatin Induces Hepatotoxicity in Diabetic Rats via Oxidative Stress, Inflammation, and Anti-Apoptotic Pathway

“…OS is an essential contributor to the etiology of multiple chronic liver disorders (CLDs). Growing evidence verifies that OS participates in the etiology of CLD triggered by chemicals as well as by drugs [22,23]. Chronic hepatic damage is characterized by cholestasis, cirrhosis, necrosis, and fibrosis.…”