**Background:** Thyroid hormones (TH), primarily thyroxine (T4) and 3,3',5'-triiodothyronine (T3), are critical regulators of energy homeostasis. The liver is a major target organ for TH action, where T3 binds to nuclear TH receptors (TRα and TRβ, with TRβ mediating hepatic effects) to regulate gene expression. Local TH availability within hepatocytes is controlled by transmembrane transporters (e.g., MCT8, MCT10, Oatps, Ntcp) and deiodinases (Dio1, Dio2, Dio3) that activate or inactivate TH. The liver also contributes to systemic TH homeostasis by secreting binding proteins (albumin, transthyretin, thyroxin-binding globulin). This review summarizes the effects of nutritional interventions on the hepatic TH system and details TH regulation of carbohydrate, lipid, and cholesterol metabolism.
**Methods:** This is a narrative review synthesizing data from animal models (primarily rats and mice), human cell culture systems (e.g., HepG2, Huh7), and some human studies. The authors evaluate the impact of fasting, energy restriction, and high-fat diets (HFD) on systemic and local hepatic TH concentrations, deiodinase activity, TH transporter expression, and conjugation enzymes (sulfotransferases and UDP-glucuronyltransferases). They also detail direct effects of T3 on key metabolic pathways in the liver, including gluconeogenesis, de novo lipogenesis, fatty acid oxidation, cholesterol synthesis, and reverse cholesterol transport.
**Key Results:** Fasting leads to a gradual decrease in serum T3 (detectable after 12 h in rats) and T4 (after 48 h) while TSH remains unaltered. Hepatic Dio1 activity decreases during fasting, while Dio3 mRNA expression and activity increase. Conjugation enzymes (Sult1a1, Ugt1a1) are upregulated via the constitutive androstane receptor (Car). T3 stimulates hepatic gluconeogenesis through Sirt1-mediated activation of FOXO1, PGC1α, and PPAR, upregulating PCK1, PDK4, and G6PC. In lipid metabolism, T3 induces de novo lipogenesis genes (Fasn, Acc1, Me1, Spot14) via TREs and non-canonical PI3K-ERK1/2-MAPK signaling, while also promoting fatty acid oxidation through PGC1α-PPARα-CPT1a signaling. T3 positively regulates cholesterol metabolism by upregulating HMG-CoA reductase, LDL receptor (Ldlr), and CYP7A1 (the rate-limiting enzyme for bile acid synthesis), while downregulating PCSK9. High-fat diet induces Dio1 mRNA expression and activity after 4 weeks, persisting up to 18 weeks. TRβ-selective thyromimetics (GC-1, KB2115) reduce total and LDL cholesterol and increase Cyp7a1 expression in Ldlr knockout mice.
**Clinical Implications:** The local hepatic TH system represents a promising therapeutic target for metabolic disorders including NAFLD, NASH, dyslipidemia, and obesity. TRβ-isoform-selective drugs like Resmetirom, which avoid TRα-mediated cardiac adverse effects, have shown efficacy in phase 3 clinical trials for NAFLD/NASH by reducing hepatic and serum lipids and triglycerides. Understanding species- and sex-specific differences in TH regulation, as well as cell-type-specific TH actions in different liver cell types (hepatocytes, Kupffer cells, hepatic stellate cells), is crucial for developing effective therapies. Future research should focus on documenting TH system alterations across different disease stages and inflammatory states to provide evidence for the clinical application of TH mimetics.