Direct effects of thyroid hormones on hepatic lipid metabolism

Abstract

It has been known for a long time that thyroid hormones have prominent effects on hepatic fatty acid and cholesterol synthesis and metabolism. Indeed, hypothyroidism has been associated with increased serum levels of triglycerides and cholesterol as well as non-alcoholic fatty liver disease (NAFLD). Advances in areas such as cell imaging, autophagy and metabolomics have generated a more detailed and comprehensive picture of thyroid-hormone-mediated regulation of hepatic lipid metabolism at the molecular level. In this Review, we describe and summarize the key features of direct thyroid hormone regulation of lipogenesis, fatty acid β-oxidation, cholesterol synthesis and the reverse cholesterol transport pathway in normal and altered thyroid hormone states. Thyroid hormone mediates these effects at the transcriptional and post-translational levels and via autophagy. Given these potentially beneficial effects on lipid metabolism, it is possible that thyroid hormone analogues and/or mimetics might be useful for the treatment of metabolic diseases involving the liver, such as hypercholesterolaemia and NAFLD.

Figure 1. Thyroid hormone effects on hepatic lipid metabolism.

Thyroid hormone stimulates lipolysis from fat stores in white adipose tissue and from dietary fat sources (high-fat diets) to generate free fatty acids (FFAs) that enter the hepatic cells via protein transporters such as fatty acid transporter protein (FATP), liver fatty acid binding protein (L-FABP) and CD36. Thyroid hormone induces de novo lipogenesis (DNL) via the transcription of several key lipogenic genes such as Acc1, Fasn, Me and Thrsp. In addition, thyroid hormone indirectly controls the transcriptional regulation of hepatic DNL by regulating the expression and activities of other transcription factors such as sterol regulatory element-binding protein 1C (SREBP1C), liver X receptors (LXRs) and carbohydrate-responsive element-binding protein (ChREBP). DNL is also driven by the influx of high levels of carbohydrate or glucose derived from high-carbohydrate diets via glucose transporters (GLUTs), which are shuttled to FFA generation. FFAs are typically esterified to triacylglycerol and subsequently packaged into VLDL for export or stored as intracellular lipid droplets. Triacylglycerol stored as lipid droplets can also be hydrolysed back to FFAs via classic lipases and lipophagy (by regulating transcription factor EB (TFEB), NAD-dependent protein deacetylase sirtuin 1 (SIRT1) and forkhead box protein O1 (FOXO1)), undergo mitochondrial β-oxidation by the activity of various co-activators or nuclear receptors (such as peroxisome proliferator-activated receptor-α (PPARα), oestrogen-related receptor-α (ERRα), fibroblast growth factor 21 (FGF21) and PPARγ co-activator 1α (PGC1α)) and target the transcription of genes such as Cpt1a, Mcad (also known as Acadm), Pdk4 and Ucp2. ↑/↓ depicts the positive or negative effect that thyroid hormone action has on the cellular process shown, respectively. OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species; TCA, tricarboxylic acid.

Figure 2. Thyroid hormone regulation of cholesterol biosynthesis and clearance.

Thyroid hormone stimulates cholesterol formation (mostly as VLDL) from its precursors and acetyl-CoA. Thyroid hormone increases the expression of Hmgcr and Fdps to promote hepatic cholesterol synthesis. Thyroid hormone also strongly induces the gene and protein expression of apolipoprotein A1 (Apo A1), scavenger receptor class B member 1 (SRB1) and sterol regulatory element-binding protein 2 (SREBP2), which then increase LDL receptor (LDLR) levels to increase cholesterol efflux from peripheral tissues to HDL through the reverse cholesterol transport pathway. Thyroid hormone increases HDL metabolism by stimulating cholesteryl ester transfer protein (CETP) activity. Thyroid hormone also increases expression of cholesterol 7α-hydroxylase (CYP7A1), which converts cholesterol into bile acids in the reverse cholesterol transport pathway. Thyroid hormone promotes the excretion of bile acids by directly increasing ATP-binding cassette subfamily G member 5/8 (Abcg5/Abcg8) transporter gene transcription. Additionally, thyroid hormone induces miR181d expression, which then decreases the expression of caudal-type homeobox protein 2 (CDX2) transcription factor and the Soat2 gene to inhibit cholesterol ester formation. ↑/↓ shows increase or decrease in thyroid hormone action, respectively. FFA, free fatty acid.