Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists

Abstract

Background-Thyroid hormones (THs) exert a strong influence on mammalian lipid metabolism at the systemic and hepatic levels by virtue of their roles in regulating circulating lipoprotein, triglyceride (TAG), and cholesterol levels, as well as hepatic TAG storage and metabolism. These effects are mediated by intricate sensing and feedback systems that function at the physiological, metabolic, molecular, and transcriptional levels in the liver. Dysfunction in the pathways involved in lipid metabolism disrupts hepatic lipid homeostasis and contributes to the pathogenesis of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and hypercholesterolemia. There has been strong interest in understanding and employing THs, TH metabolites, and TH mimetics as lipid-modifying drugs. Summary-THs regulate many processes involved in hepatic TAG and cholesterol metabolism to decrease serum cholesterol and intrahepatic lipid content. TH receptor β analogs designed to have less side effects than the natural hormone are currently being tested in phase II clinical studies for NAFLD and hypercholesterolemia. The TH metabolites, 3,5-diiodo-L-thyronine (T2) and T1AM (3-iodothyronamine), have different beneficial effects on lipid metabolism compared with triiodothyronine (T3), although their clinical application is still under investigation. Also, prodrugs and glucagon/T3 conjugates have been developed that direct TH to the liver. Conclusions-TH-based therapies show clinical promise for the treatment of NAFLD and hypercholesterolemia. Strategies for limiting side effects of TH are being developed and may enable TH metabolites and analogs to have specific effects in the liver for treatments of these conditions. These liver-specific effects and potential suppression of the hypothalamic/pituitary/

New drugs for non‐alcoholic steatohepatitis

“…The thyroid hormone receptor β (THR β) is highly expressed in hepatocytes and is responsible for regulating the metabolic pathways in the liver that are frequently impaired in NAFLD and NASH. 13 Resmetirom (MGL-3196, Madrigal Pharmaceuticals Inc), a highly selective THR β agonist, has been developed to target dyslipidemia but has also been shown to reduce hepatic steatosis in fat-fed rats, improving insulin sen- and did not result in study withdrawal. 15 A phase 3 in patients with NASH and fibrosis is now recruiting (https ://clini caltr ials.gov/ct2/show/NCT03 900429).…”

Thyroid Hormones and Thyromimetics: A New Approach to Nonalcoholic Steatohepatitis?

“…Thyroid hormones (THs), T 4 , and the more biologically active form, T 3 , stimulate fatty acid β-oxidation and oxidative phosphorylation in the liver. (2) Numerous studies have shown an inverse relationship between serum TH levels and NAFLD given that patients with hypothyroidism and subclinical hypothyroidism have increased risk for NAFLD and vice versa. (3) Transcriptomes of liver samples obtained from bariatric surgery patients also showed that the most prominent altered gene set was associated with TH action.…”

“…(4) Additionally, T 3 and several thyromimetics decreased intrahepatic triglycerides in rodent models of hepatosteatosis. (2) Although TH increases the transcription of carnitine palmitoyl-transferase 1alpha (a carrier protein that promotes fatty acid uptake into mitochondria) and adipose triglyceride lipase (a lipase that converts triglycerides to fatty acids), hepatic autophagy of fat droplets and their conversion to free fatty acids within fused autolysosomes (lipophagy) appears to be crucial for TH-mediated β-oxidation of fatty acids. (5) Additionally, TH maintains mitochondria quality during this process by autophagy of mitochondria (mitophagy) and mitochondrial biogenesis.…”

Molecular links between non-alcoholic fatty liver disease and hepatocellular carcinoma

“…NAFLD is also associated with decreased sensitivity to thyroid hormones [116] and both NAFLD and HCC are associated with hypothyroidism in humans [117,118] . Furthermore, thyroid hormone treatment decreases hepatosteatosis and the progression of NAFLD in both rodents and humans [119] . Several new studies provide evidence for a potential role of androgen and the androgen receptor pathway in the development of NASH-related HCC and in the treatment of HCC [120] .…”