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. 2023 May 1;19(1):60–70. doi: 10.17925/EE.2023.19.1.60

Figure 3: Proposed hepatocyte pathways activated by thyroid hormone receptor-β agonists in relation to non-alcoholic steatohepatitis.

Figure 3:

It is hypothesized that THR-β agonists, such as resmetirom, activate THR-β, an abundant nuclear hormone receptor found hepatocytes. It is hypothesized that activating THR-β modulates several genes that promote uptake of free fatty acids from both external sources (CPT1), as well as increased production and uptake of internal free fatty acids from de novo lipogenesis (ACC1, FAS) and lipophagy. Increased mitochondrial biogenesis (CPT1a, mcad, PDk4, UCP2) and mitophagy of unhealthy mitochondria increase capacity to handle and burn the increased flow of free fatty acids. While increased cholesterol is produced due to upregulation of HMGCoA reductase, bile acid synthesis increases through increased CYP7A1 and excretion, and LDL uptake by the liver increases by induction of the LDL-R. As a result, fatty acid β-oxidation, mitochondrial biogenesis, de novo lipogenesis, cholesterol and bile acid synthesis all increase, and LDL cholesterol levels decrease. SHBG, which transports androgens and oestrogens in blood and regulates their access to target tissues, is also a known downstream target of THR-β and may be a biomarker of target engagement.

Used with permission from ©Mount Sinai Health System.

ACC1 = acetyl coenzyme A carboxylase 1; acetylCoA = acetyl coenzyme A; acylCoA = acyl coenzyme A; CPT1 = carnitine palmitoyltransferase I; CYP7A1 = cholesterol 7 alphahydroxylase; CoA = coenzyme A; FABP = fatty acid binding protein; FAS = fatty acid synthase; FFA = free fatty acids; HMGCoA = 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase; LDL = low-density lipoprotein; LDL-R = low-density lipoprotein receptor; mcad = medium-chain acyl-coenzyme A dehydrogenase; Pdk4 = pyruvate dehydrogenase kinase 4; ROS = reactive oxygen species; RXR = retinoid X receptor; SHPG = sex hormone binding globulin; T3 = triiodothyronine; TCA = tricarboxylic acid; TG = triglycerides; THR-β = thyroid hormone receptor β; TRE = tetracycline-responsive element; UCP2 = uncoupling protein 2; VLDL = very-low-density lipoprotein.