Thyroid Hormone Receptor-β Agonists in NAFLD Therapy: Possibilities and Challenges

Nonalcoholic fatty liver disease (NAFLD) is a progressive metabolic liver disease with an unknown pathogenesis and no FDA-approved drug treatment to date. Hypothyroidism has been identified as a risk factor for NAFLD as thyroxine is required for regulating metabolism in adults. Thyroxine has been shown to reduce fat in the livers of murine models with experimentally induced NAFLD. The use of synthetic thyroxine has been shown to increase lipid metabolism leading to weight loss; however, thyroxine has also been shown to cause many side effects, especially in the heart. Overcoming these cardiac side effects involves designing agonists specific to one of the 2 gene subtypes for the thyroid hormone (TH) receptor (TR), TRβ. While the other TH receptor subtype, TRα, is mainly expressed in the heart and is responsible for thyroxine's cardiac function, TRβ is mainly expressed in the liver and is involved in liver function. Using TRβ-specific agonists to treat NAFLD can prevent cardiac and other adverse side effects. Several TRβ-specific agonists have shown positive therapeutic effects in NAFLD animal models and have entered clinical trials. We seek to provide a comprehensive updated reference of TRβ-specific agonists in this review and explore the future therapeutic potential of TRβ-specific activation in the treatment of NAFLD.