Thyroid hormone action and liver disease, a complex interplay

Abstract

Thyroid hormone action is involved in virtually all physiological processes. It is well known that the liver and thyroid are intimately linked, with thyroid hormone playing important roles in de novo lipogenesis, beta-oxidation (fatty acid oxidation), cholesterol metabolism, and carbohydrate metabolism. Clinical and mechanistic research studies have shown that thyroid hormone can be involved in chronic liver diseases, including alcohol-associated or NAFLD and HCC. Thyroid hormone action and synthetic thyroid hormone analogs can exert beneficial actions in terms of lowering lipids, preventing chronic liver disease and as liver anticancer agents. More recently, preclinical and clinical studies have indicated that some analogs of thyroid hormone could also play a role in the treatment of liver disease. These synthetic molecules, thyromimetics, can modulate lipid metabolism, particularly in NAFLD/NASH. In this review, we first summarize the thyroid hormone signaling axis in the context of liver biology, then we describe the changes in thyroid hormone signaling in liver disease and how liver diseases affect the thyroid hormone homeostasis, and finally we discuss the use of thyroid hormone-analog for the treatment of liver disease.

FIGURE 1

Genomic and nongenomic pathways of TH action. Genomic effects of TH (left side of figure). TR dimerizes with other nuclear receptors (in this case RXR) to recruit a set of coactivators forming a mediator-like complex that increase histone acetyltransferase activity (SRCs, PCAF) increasing the transcriptional activity of target genes. In the absence of thyroid hormone, TR/nuclear receptors dimers can recruit corepressors (NCoR, SMRT) with HDAC3 activity, reducing the transcriptional activity of target genes. SRCs and PCAF are histone acetyltransferases and PRMT1 is a histone methyltransferase. Nongenomic effect of TH (left side of figure). TH affect multiple physiological activities by means of interactions with S1 and S2 αvβ3 integrin. The interaction between T4 and S2 αvβ3 integrin, leading to regulation of PI3K, MAPK1/2, and ERK-1/2 by means of PLC and PKCα, promoting phosphorylation of nucleoproteins and modulation of intracellular protein trafficking. ERK-1/2 activity can activate the sodium proton exchanger (Na+/H+ ) in the plasma membrane. S1 αvβ3 integrin recognizes T3 and activates the PI3K pathway leading to direct trafficking of TRα1 from the cytoplasm to the nucleus and transcriptional activity of the target gene, HIF-1α. Furthermore, activation of the PI3K/Akt/PKB pathway can be rapidly stimulated by means of T3 interactions with TRβ1 or TRα1 and initiates downstream target gene transcription including HIF-1α and GLUT1. Abbreviations: ERK, extracellular signal-regulated kinase; HDAC3, histone deacetylase 3; HIF, hypoxia inducible factor; NCoR, nuclear receptor co-repressor; PCAF, P300/CBP-associated factor; PI3K, phosphatidylinositol-3-kinase; RXR, retinoid X receptor; SMRT, silencing mediator for retinoid or thyroid hormone receptors; SRCs, steroid receptor coactivator; TH, thyroid hormone; TR, thyroid hormone receptor.

FIGURE 2

Hepatic FFAs metabolism and TH effect in hepatocytes. Thyroid hormone stimulates lipolysis from fat stores in white adipose tissue and from dietary fat sources to generate FFAs that enter the hepatic cells by means of protein transporters such as fatty acid–binding protein (FABP), calcium-independent phospholipase A2 Beta (iPLA2-β), caveolin-1, and fatty acid transporter (FAT/CD36). 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 hydrolyzed back to FFAs by means of classic lipases and lipophagy by regulating transcription factors (SIRT1, FOXO1), various coactivators or nuclear receptors such as (PPARα, FGF21, and PGC1α) and target the transcription of genes such as Cpt1a, Acadm, Pdk4, and Ucp2. Thyroid hormone induces DNL by means of the transcription of several key lipogenic genes such as Acaca, Fas, 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 SREBP1C, LXRs, and ChREBP. Abbreviations: CHREBP, carbohydrate-responsive element-binding protein; DNL, de novo lipogenesis; FABP, fatty acid-binding protein; FAT/CD36, fatty acid translocase; FFA, free fatty acid; FOXO1, forkhead box protein O1; LXR, liver X receptor; PGC1α, PPARγ co-activator 1α; PPAR, peroxisome proliferator-activated receptor; SREBP, sterol regulatory element-binding protein; SIRT1, NAD-dependent protein deacetylase sirtuin 1; TH, thyroid hormone.

FIGURE 3

TH effect on cholesterol metabolism. TH increases the expression of HMGCR and FDPS to promote hepatic cholesterol synthesis. TH is involved also in the cholesterol uptake from peripheral tissue inducing the gene and protein expression of SRBP1, SREBP2, Apo A1, LDLR, CETP, LDLR, LPL, and HL. TH is also involved in the reverse cholesterol transport pathway increasing expression of CYP7A1. Furthermore, TH increases the efflux of bile by stimulating Abcg5/Abcg8 gene transcription. Additionally, TH can negatively modulate cholesterol ester formation by means of CDX2 and SOAT2. Abbreviations: Abcg, ATP-binding cassette subfamily G member; APOA1, apolipoprotein A1; CDX2, caudal-type homeobox 2; CETP, cholesteryl ester transfer protein; CYP7A1, cholesterol 7α-hydroxylase; FDPS, farnesyl diphosphate synthase; HL, hepatic lipase; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; LDLR, LDL receptor; LPL, lipoprotein lipase; ; SOAT2, sterol O-acyltransferase 2; SRB1, scavenger receptor class B member 1; SREBP, sterol regulatory element-binding protein; TH, thyroid hormone.

FIGURE 4

TH action promotes differentiation and inhibits neoplastic proliferation in hepatocytes, while hypothyroidism and somatic mutations in the TRα and TRβ genes are involved in HCC progression. TH action is also involved in HCC inhibition by means of Wnt/β-catenin/PDK1/PGC1α or Wnt/β-catenin/DKK-4 pathway. TH signaling indirectly activates PPARγ, that is also involved in HCC inhibition by means of cell cycle arrest and apoptosis. Abbreviations: DKK, Dickkopf; PDK, pyruvate dehydrogenase kinase; PGC1α, PPARγ co-activator 1α; PPAR, peroxisome proliferator-activated receptor; TH, thyroid hormone; TR, thyroid hormone receptor.