Hepatic mitochondrial reductive stress in the pathogenesis and treatment of steatotic liver disease.

In steatotic liver diseases (SLDs), including metabolic dysfunction-associated SLD and alcohol-associated liver disease, the excessive hepatic metabolism of lipids and alcohol leads to an increase in hepatic mitochondrial reductive stress, which in turn contributes to the development of SLD. Recent genetic studies conducted on both humans and mice have provided further evidence highlighting the key role played by hepatic mitochondrial reductive stress in the pathogenesis of SLD. Several pharmaceutical agents currently in development for the treatment of SLD, such as peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, thyroid hormone receptor agonists, acetyl-CoA carboxylase (ACC) inhibitors, and mitochondrial uncouplers, share an under-recognized common characteristic in that they decrease hepatic mitochondrial reductive stress. A more comprehensive understanding of hepatic mitochondrial reductive stress could help elucidate disease pathogenesis and facilitate the identification of new therapeutic approaches. Steatotic liver diseases (SLDs) affect one-third of the population, but the pathogenesis underlying these diseases is not well understood, limiting the available treatments. A common factor in SLDs is increased hepatic mitochondrial reductive stress, which occurs as a result of excessive lipid and alcohol metabolism. Recent research has also shown that genetic risk factors contribute to this stress. This review aims to explore how these risk factors increase hepatic mitochondrial reductive stress and how it disrupts hepatic metabolism, leading to SLDs. Additionally, the review will discuss the latest clinical studies on pharmaceutical treatments for SLDs, specifically peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, thyroid hormone receptor (THR) agonists, acetyl-CoA carboxylase (ACC) inhibitors, and mitochondrial uncouplers. These treatments have a common effect of decreasing hepatic mitochondrial reductive stress, which has been largely overlooked. [ABSTRACT FROM AUTHOR]