97-OR: Antidiabetic TIX100 Improves NAFLD/NASH in Mice With and Without Diabetes and Obesity

Abstract

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are often associated with diabetes, but are becoming an even bigger world-wide epidemic with over 1 billion people affected. Nevertheless, while some diabetes medications such as glucagon-like peptide 1 and peroxisome proliferator-activated receptor agonists have shown some beneficial effects in the context of NAFLD with diabetes, no approved therapy is currently available for NAFLD/NASH. Interestingly, the new antidiabetic small molecule thioredoxin-interacting protein (Txnip) inhibitor, TIX100, effectively protected obese and diabetic db/db mice against steatosis. TIX100 also significantly reduced the elevated expression levels of lipogenic genes found in db/db livers, many of which have also been shown to be elevated in human NAFLD and are being pursued as potential therapeutic targets. Importantly, the beneficial effects of TIX100 were not due to any weight loss as the severe obesity of the db/db mice was not affected by the treatment. In contrast, TIX100 did demonstrated strong antidiabetic effects and normalized the blood glucose of db/db mice to the levels observed in lean control animals. Therefore, to address the question of whether TIX100 would still be effective in the absence of diabetes, obesity and any genetic leptin-receptor deficiency, we next used a validated choline-deficient, amino acid-defined, high-fat diet to induce NASH. Indeed, compared to control chow, this diet significantly increased plasma liver enzymes indicating liver injury, led to elevated hepatic expression of inflammatory and fibrogenic markers and resulted in clear histological changes, demonstrating lipid accumulation and steatosis as well as pronounced fibrosis and upregulation of liver macrophages. Excitingly, TIX100 treatment blunted or improved all these pathological changes. Thus, TIX100 may not only be effective in diabetes, but may also provide an attractive novel approach for NAFLD/NASH. Disclosure S. Jo: None. J. Chen: None. G. Jing: None. K.M. Habegger: Research Support; Eli Lilly and Company, Novo Nordisk. Consultant; Glyscend Inc. Stock/Shareholder; Glyscend Inc. Research Support; Glyscend Inc. A. Shalev: Other Relationship; TIXiMED. Funding National Institutes of Health (R01DK078752); Human Islet Research Network (U01DK120379)