Abstract
Non-alcoholic fatty liver disease (NAFLD) is the fastest-growing liver disease in the world. Despite targeted agents which are needed to provide permanent benefits for patients with NAFLD, no drugs have been approved to treat NASH. Thyroid hormone is an important signaling molecule to maintain normal metabolism, and in vivo and vitro studies have shown that regulation of the 3,5,3’-triiodothyronine (T3)/ thyroid hormone receptor (TR) axis is beneficial not only for metabolic symptoms but also for the improvement of NAFLD and even for the repair of liver injury. However, the non-selective regulation of T3 to TR subtypes (TRα/TRβ) could cause unacceptable side effects represented by cardiotoxicity. To avoid deleterious effects, TRβ-selective thyromimetics were developed for NASH studies in recent decades. Herein, we will review the development of thyroid hormones and synthetic thyromimetics based on TR selectivity for NAFLD, and analyze the role of TR-targeted drugs for the treatment of NAFLD in the future.
Highlights
Non-alcoholic fatty liver disease (NAFLD) refers to the clinical syndrome of liver diseases caused by excessive deposition of fat in hepatocytes under non-alcoholic or other special liver damaging factors, including simple steatosis (SFL), non-alcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis [1,2]
In order to find out whether T2 reduces liver fat accumulation is a direct effect on the liver, Grasselli and co-workers studied the ability of T2 to reduce excess lipid in hepatocytes separated and treated with free fatty acid (FFA), and the results showed that added T2 or T3 in the FFA processing “fatty hepatocyte” could directly lead to the extra fat reduction of hepatocytes, by reducing hepatocellular fat accumulation related factors, which include: (i) lipid content and lipid droplet diameter; (ii) expression of Peroxisome proliferator-activated receptor (PPAR)-γ and PPAR-δ; and (iii) activities of CoA oxidase and antioxidant enzyme [90]
In phase II clinical trials, MGL-3196 had good effects on plasma lipids compared with placebo: low-density lipoprotein cholesterol (LDL-C) was reduced by 22.3%; triglyceride was reduced by 30.8%; lipoprotein (a) had a 37.9% lower lipid, and adverse events are mild, even a moderate adverse event to keep a balance between groups such as the increased incidence of mild temporary diarrhea caused, but not significantly affects for the TSH levels, bone mineral density, cardiovascular or the insulin sensitivity [135]
Summary
Non-alcoholic fatty liver disease (NAFLD) refers to the clinical syndrome of liver diseases caused by excessive deposition of fat in hepatocytes under non-alcoholic or other special liver damaging factors, including simple steatosis (SFL), non-alcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis [1,2]. Given the serious threat to human life and health of NAFLD, in terms of prevention and control, it was recommended that people keep a good diet and living habits as far as possible, and many research results showed that diet and exercise, such as losing weight, reducing body fat, or keeping happy, and so on, could play a positive role to inhibit the development of NAFLD [13,21,22,23,24], but there is little benefit in patients with end-stage liver disease and it is difficult to get effective and lasting results by lifestyle intervention. Of note, increasing evidence showed that THs have an obvious effect on ameliorating NAFLD under the thyroid hormone receptor (TR) which has an organ-targeting property [63,64,65]. The whole process will be reviewed below, and the current research advance and future direction will be analyzed
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