Investigating the role of TSC22D4 phosphorylation in metabolic control

Abstract

Obesity is a chronic and complex disease of excessive fat deposits that can put the patients at high risk for developing metabolic complications such as type 2 diabetes, heart disease and cancer. Excessive accumulation of lipids in the liver also causes non-alcoholic fatty liver disease (NAFLD) which can progress further into non-alcoholic steatohepatitis (NASH) and liver fibrosis and eventually liver cancer when left untreated. The recently FDA approved Resmetirom is the only medication that exists for anti-NASH treatment in the market, which shows only around 30% efficacy for NASH resolution with frequent side effects (Harrison et al, N Engl J Med 2024), indicating that patients are in need of better medications that require a much better understanding of molecular mechanisms that underlie the development of NAFLD and NASH/ liver fibrosis. Recently we identified hepatic TSC22D4 as a critical controller of diabetic hyperglycemia and insulin resistance (Ekim Üstünel et al, Nat Comm 2016). Obese patients with NAFLD and NASH have elevated TSC22D4 expression, positively correlating with liver disease progression (Wolff et al, Mol Met 2022). Our functional studies with TSC22D4 hepatocyte specific (TSC22D4hepKO) knockout mice indicated that TSC22D4 has a causal role in excessive lipid accumulation, inflammation, apoptosis in the liver causing NAFLD and NASH-related pathologies by impairing mitochondrial function (Wolff et al, Mol Met 2022). Unlike defined functions of TSC22D4 above, we know very little of its upstream regulators. Hence, we aimed to elucidate the intricate regulatory mechanism for controlling TSC22D4 function that will be helpful in the potential development of a novel therapeutic approach for the treatment of NAFLD/NASH.