Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): New Perspectives on an Evolving Epidemic

The absence of a unifying pathogenetic mechanism in metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), has significantly hindered therapeutic progress. Appreciation that the delivery of excessive amounts of calories to the liver via the portal circulation might be a key parallel between MASLD and the twin steatotic liver disease, alcohol-related liver disease (ALD), establishes a consolidated framework that could guide rational drug design and precise therapeutic approaches. This review contends that, in both ALD and MASLD, the unique dual blood supply to the liver, from both portal vein and hepatic artery as well as the distinctive blood flow control physiology, prevents hepatic arterial oxygen delivery from adequately compensating for the increased metabolic demands induced by excess caloric intake—alcohol in ALD and food in MASLD—resulting in hepatocellular injury. Over four decades ago, Lautt postulated that this ‘oxygen-nutrient mismatch’ could play a role in ALD. We have extended this paradigm to MASLD, theorizing that analogous mechanisms may be involved in both conditions. Evidence that comorbidities, which are associated with recurrent episodes of hypoxemia, such as obstructive sleep apnea (OSA), exacerbate MASLD progression, supports this. ALD is less strongly linked to metabolic syndrome than MASLD. This may be due to inherent differences in hepatic substrate processing. Carbohydrates, lipids, and proteins undergo diverse and flexible cytosolic metabolic pathways, especially under metabolic stress. In contrast, hepatic ethanol metabolism is predominantly linear and obligately oxidative, providing limited metabolic adaptability. Future perspectives could focus on rectifying the imbalance between hepatic oxygen delivery and nutrient availability. This might be accomplished by attenuating hepatic caloric excess using emerging pharmacotherapies for weight reduction, augmenting hepatic oxygenation through hyperbaric oxygen therapy, or increasing hepatic arterial blood flow with agents such as obeticholic acid. Furthermore, enhancement of hepatic basal metabolic activity with thyroid hormone receptor-β agonists, like resmiritom may confer similar therapeutic effects.