Omaveloxolone and TX63682 are hepatoprotective in the STAM mouse model of nonalcoholic steatohepatitis

Abstract

Omaveloxolone is a potent activator of Nrf2, a master transcriptional regulator of a multitude of cytoprotective functions, including antioxidative, anti‐inflammatory, and mitochondrial bioenergetic effects. Some of the most potent known effects of Nrf2 involve hepatoprotective functions. The purpose of this study was to evaluate the effects of omaveloxolone and TX63682, a closely related structural analog with similar oral bioavailability, in the STAM mouse model of nonalcoholic steatohepatitis (NASH). C57Bl/6 mice received a single subcutaneous injection of streptozotocin two days after birth and were fed a high‐fat diet from 4 to 9 weeks of age. Omaveloxolone and TX63682 were orally administered at doses of 1, 3, and 10 mg/kg/d from 6 to 9 weeks of age. Consistent with the beneficial effects of Nrf2 on hepatoprotection and improved lipid handling, both omaveloxolone and TX63682 decreased hepatic fat deposition, hepatocellular ballooning, inflammatory cell infiltration, and collagen deposition. Omaveloxolone and TX63682 also improved blood glucose control, as evidenced by reductions in nonfasting blood glucose and glycated hemoglobin A1C concentrations. Reductions in liver and serum triglycerides with omaveloxolone and TX63682 treatment were also observed. Both omaveloxolone and TX63682 decreased leptin and increased adiponectin in serum, which is consistent with the anti‐inflammatory and antifibrotic effects observed in the liver. These results were associated with significant induction of Nrf2 target gene expression in the liver, including NAD(P)H:quinone oxidoreductase 1, sulfiredoxin 1, and ferritin heavy chain 1. Overall, these data suggest that omaveloxolone and related Nrf2 activators may be useful for the treatment of NASH.

Effects of Bardoxolone Methyl on Hepatic Enzymes in Patients with Type 2 Diabetes Mellitus and Stage 4 CKD

“…Alternatively, transcriptional regulation of aminotransferases in vivo may be influenced by disease status, and all animals used for good laboratory practice toxicity studies were naïve and healthy. Supporting this hypothesis, analogs of bardoxolone methyl mildly increased serum aminotransferase activity while also significantly improving liver histology in an animal model of nonalcoholic steatohepatitis 35 …”

“…Supporting this hypothesis, analogs of bardoxolone methyl mildly increased serum aminotransferase activity while also significantly improving liver histology in an animal model of nonalcoholic steatohepatitis. 35 The profile of transient and reversible increases in aminotransferases with bardoxolone methyl might suggest that a form of possible drug tolerance or adaptation develops, as is often seen with several other classes of drugs, notably the statins. [36][37][38] It is well-known that such drug tolerance is seen in a relative minority of patients, typically ranging from 5% to 25%.…”

Cache Domain Containing 1 Is a Novel Marker of Non-Alcoholic Steatohepatitis-Associated Hepatocarcinogenesis

“…Furthermore, potent activators of transcriptional regulator Nrf2 with numerous cytoprotective functions were shown to be useful for the treatment of NASH in STAM mice model. For instance, omaveloxolone has been reported to suppress leptin and elevate adiponectin levels in serum and possess antifibrotic activity in the liver [ 37 ]. In addition, Liebig et al discovered that increased n-3 polyunsaturated fatty acids (PUFA) ratios lead to improved survival and attenuated tumor progression in STAM mice, thus, suggesting PUFA to become new therapeutic options against NAFLD-related tumorigenesis [ 38 ].…”

Oxidative stress and redox signaling in CRPC progression: therapeutic potential of clinically-tested Nrf2-activators

“…Due to its effects in suppressing oxidative stress, omaveloxolone has been used in Friedreich’s ataxia models to suppress mitochondrial defects [ 286 ] and to increase the regenerative capacity of diabetic wounds [ 287 ] . By suppressing chronic inflammation and immune dysfunction, this Nrf2 activator has also been shown to attenuate osteoclast production [ 288 ] and nonalcoholic steatohepatitis (NASH) [ 289 ] . A third oleic acid derivative currently under early stage clinical trial is 10-nitro oleic acid (NO2-OA) or CXA-10 [ 290 ] .…”