Integrative metabolism in MASLD and MASH: Pathophysiology and emerging mechanisms

The liver acts as a central metabolic hub, integrating signals from the gastrointestinal tract and adipose tissue to regulate carbohydrate, lipid, and amino acid metabolism. Gut-derived metabolites, such as acetate and ethanol, and non-esterified fatty acids from white adipose tissue influence hepatic processes, which rely on mitochondrial function to maintain systemic energy balance. Metabolic dysregulation caused by obesity, insulin resistance, and type 2 diabetes disrupts these pathways, leading to metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). In this review, we explore the metabolic fluxes within the gut-adipose tissue-liver axis, focusing on the pivotal role of de novo lipogenesis, dietary substrates like glucose and fructose, and changes in mitochondrial function during MASLD progression. We also highlight the contributions of white adipose tissue insulin resistance and impaired mitochondrial dynamics to hepatic lipid accumulation. Further understanding how the interplay between substrate flux from the gastro-intestinal tract integrates with adipose tissue and intersects with structural and functional alterations to liver mitochondria will be important to identify novel therapeutic targets and advance the treatment of MASLD and MASH.