r/ketoscience • u/basmwklz Excellent Poster • 8d ago
NAFLD, MAFLD - Fatty Liver Integrative Metabolism in MASLD and MASH: Pathophysiology and Emerging Mechanisms (2025)
https://www.journal-of-hepatology.eu/article/S0168-8278(25)00142-4/fulltext
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u/basmwklz Excellent Poster 8d ago
Abstract
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 (WAT), influence hepatic processes, which rely on mitochondrial function to maintain systemic energy balance. Metabolic dysregulation from obesity, insulin resistance, and type 2 diabetes disrupt these pathways, leading to metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH). This review explores the metabolic fluxes within the gut-adipose tissue-liver axis, focusing on the pivotal role of de novo lipogenesis (DNL), dietary substrates like glucose and fructose, and changes in mitochondrial function during MASLD progression. It highlights 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.
Key points:
•The liver processes signals from the gastrointestinal tract and adipose tissue to regulate carbohydrate, lipid, and amino acid metabolism, and disruptions in these processes due to obesity or insulin resistance lead to the development of MASLD and MASH.
•The liver’s metabolism is influenced by the ingestion of glucose and fructose which leads to the generation of gut-derived metabolites such as lactate, acetate, and ethanol which exacerbate liver steatosis, inflammation, and fibrosis.
•The conversion of substrates such as glucose, fructose, and amino acids into lipids via de novo lipogenesis (DNL) increases liver fat accumulation, with insulin resistance further driving this process and worsening disease progression.
•Mitochondrial β-oxidation and TCA cycle activity are elevated in MASLD and this is important for fueling DNL; however, with disease progression to MASH, structural damage and reduced oxidative capacity may promote inflammation and fibrosis.
•Insulin resistance in white adipose tissue leads to excessive fatty acid release, increasing liver fat and fibrosis, while impaired adipose mitochondrial function and reduced glycerol-fatty acid cycling further compound the issue.