THE LIVER plays a fundamental role in regulating metabolism, integrating signals from the gut and adipose tissue to manage nutrient processing and storage. As the first organ to receive nutrient-rich blood from the gastrointestinal tract, the liver modulates glucose, lipid, and amino acid metabolism, responding dynamically to food intake and energy demands. Signals from gut-derived metabolites, such as lactate and acetate, alongside non-esterified fatty acids (NEFAs) and adipokines from adipose tissue, influence hepatic lipid synthesis and oxidation.
Metabolic-dysfunction-associated steatotic liver disease (MASLD) arises from excessive intrahepatic triglyceride accumulation, often progressing to metabolic-dysfunction-associated steatohepatitis (MASH) when inflammation and hepatocyte damage occur. In MASLD, an increase in de novo lipogenesis (DNL) and heightened NEFA flux from adipose tissue contribute to abnormal lipid accumulation. Hepatocytes, responsible for fatty acid uptake and triglyceride synthesis, normally maintain a balance between lipid storage and export via very low-density lipoproteins (VLDLs). However, disruptions in these processes, often driven by insulin resistance and mitochondrial dysfunction, exacerbate disease progression.
Mitochondrial impairment is a key factor in MASLD and MASH development, affecting oxidative capacity and energy homeostasis. Structural abnormalities in mitochondria reduce their ability to metabolise fatty acids efficiently, leading to increased lipid accumulation and oxidative stress. Additionally, insulin resistance alters metabolic flux, promoting excessive lipid synthesis while impairing glucose metabolism. These disruptions collectively drive hepatic inflammation and fibrosis, worsening disease severity.
Therapeutic strategies targeting metabolic pathways are crucial for MASLD and MASH management. GLP-1 receptor agonists improve insulin sensitivity, suppress appetite, and promote weight loss, thereby reducing lipid accumulation in the liver. Thyroid hormone receptor-beta (THRβ) agonists enhance fatty acid oxidation and mitochondrial function, offering another potential treatment avenue. Future research should focus on understanding the interplay between metabolic substrates like lactate, acetate, and amino acids, and their roles in liver fibrosis and disease progression. Investigating zonal metabolic variations within the liver and interorgan crosstalk, particularly with adipose tissue, may uncover novel therapeutic targets. Mitochondria-targeted interventions that modulate substrate demand while reducing NEFA release could also hold promise in addressing the metabolic and inflammatory drivers of MASH.
Katie Wright, EMJ
Reference
Steinberg GR et al. Integrative metabolism in MASLD and MASH: pathophysiology and emerging mechanisms. J Hepatol. 2025;DOI:10.1016/j.jhep.2025.02.033.
