Quick glance at 'metabolic dysfunction associated steatotic liver disease' therapeutics: Targets, trials, and trends

Figure 1 Natural history and pathogenesis of metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis. The metabolic dysfunction-associated steatotic liver disease spectrum extends from simple steatosis to steatohepatitis to fibrosis and cirrhosis and could predispose to hepatocellular carcinoma. The "multiple hit" hypothesis best explains the pathogenesis, although the sequence or influence of each hit is unclear and may vary between individual patients.

Figure 2 Insulin resistance and metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis. Insulin resistance promotes adipolysis, culminating in a flux of circulating free fatty acids (FFA). Within the liver, FFAs are esterified to form triglycerides, which are deposited in the hepatocyte cytosol, leading to hepatic steatosis. Alternatively, they interact with apolipoproteins to form very low-density lipoproteins. The free fatty acids also undergo fatty acid oxidation, primarily in the mitochondria. Insulin resistance is associated with mitochondrial dysfunction and reduced hepatic fatty acid oxidation. The hyperinsulinemia and hyperglycemia, in the setting of insulin resistance, further enhance hepatic de novo lipogenesis via sterol regulatory element-binding protein 1 and carbohydrate response element binding protein, respectively. FFA: Free fatty acids; T2DM: Type 2 diabetes mellitus; VLDL: Very-low-density lipoprotein.

Figure 3 The nuclear thyroid hormone receptor β - retinoid X receptor heterodimer is physiologically activated by triiodothyronine (T3). Resmetirom, a liver-directed agonist of thyroid hormone receptor β (THRβ), interacts with the THRβ - retinoid X receptor heterodimer to activate the thyroid hormone response elements, resulting in selective messenger ribonucleoprotein (mRNA) transcription and protein translation. The resultant proteins promote mitophagy (the removal of damaged mitochondria), mitochondrial biogenesis, and mitochondrial fatty acid oxidation, allowing for improved clearance of free fatty acids. It suppresses hepatic de novo lipogenesis by downregulating sterol regulatory element-binding protein 1c, fatty acid synthase, and acetyl-CoA carboxylase 1. Additional proteins: Cytochrome P450, family 7, subfamily A, polypeptide 1 increases bile acid synthesis; hydroxymethylglutaryl-CoA reductase increases cholesterol synthesis; the low-density lipoprotein receptor increases hepatic low-density lipoproteins uptake. RXR: Retinoid X receptor; TRE: Thyroid hormone response elements; LDL: Low-density lipoproteins; LDL-R: Low-density lipoprotein receptor; THRβ: Thyroid hormone receptor β.