Metabolic-associated fatty liver disease (MASLD) and metabolic-associated steatohepatitis (MASH are linked to a series of complex processes in the liver, involving intricate molecular mechanisms. Here's a deeper dive:
De Novo Lipogenesis (DNL): The liver overproduces fatty acids from non-fat sources like carbohydrates, driven by enzymes like sterol regulatory element-binding protein 1 (SREBP-1). Clinically, targeting SREBP-1 could be a potential therapeutic strategy.
Increased Lipolysis: Insulin resistance in fat tissue triggers the release of free fatty acids (NEFAs) into the bloodstream, delivered to the liver by proteins like cluster of differentiation 36 (CD36). Improving insulin sensitivity through lifestyle modifications and potentially pharmacological interventions can help reduce NEFA influx into the liver.
Hepatic Triglyceride Synthesis: The liver assembles triglycerides (TAGs) and diacylglycerols (DAGs) through the re-esterification of NEFAs, facilitated by enzymes like diacylglycerol acyltransferase (DGAT). Inhibiting DGAT is a promising therapeutic approach currently under investigation.
Altered Very Low-Density Lipoprotein (VLDL) Secretion: Impaired VLDL secretion, which transports fats away from the liver, worsens lipid accumulation. Microsomal triglyceride transfer protein (MTP) plays a vital role in VLDL assembly and secretion. Modulating MTP activity could be a potential therapeutic target.
Understanding these molecular mechanisms is crucial for developing targeted therapies for MASLD and MASH. By unraveling these complex pathways, researchers and clinicians are working towards developing effective treatments for MASLD and MASH.
Carli F, Della Pepa G, Sabatini S, Vidal Puig A, Gastaldelli A. Lipid Metabolism in MASLD and MASH: from mechanism to the clinic. JHEP Reports. 2024:101185.
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