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TEM-976; No.

of Pages 8

Review

Thyroid hormone regulation of hepatic


lipid and carbohydrate metabolism
Rohit A. Sinha1*, Brijesh K. Singh1*, and Paul M. Yen1,2
1
Cardiovascular and Metabolic Disorders Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169547,
Singapore
2
Sarah W. Stedman Nutrition and Metabolism Center, Departments of Medicine and Pharmacology and Cancer Biology,
Duke University Medical Center, Durham, NC 27705, USA

Thyroid hormone (TH) has important roles in regulating with non-alcoholic fatty liver disease (NAFLD) [5], a condi-
hepatic lipid, cholesterol, and glucose metabolism. Re- tion that is estimated to occur in more than 30% of American
cent findings suggest that clinical conditions such as adults, many of whom also have obesity and/or type 2
non-alcoholic fatty liver disease and type 2 diabetes diabetes mellitus (T2DM) [6]. Hypothyroidism is also con-
mellitus, which are associated with dysregulated hepat- sidered a risk factor for developing NAFLD because hypo-
ic metabolism, may involve altered intracellular TH ac- thyroid patients have an increased prevalence of NAFLD
tion. In addition, TH has key roles in lipophagy in lipid [5,7], and both hypothyroidism and NAFLD are associated
metabolism, mitochondrial quality control, and the reg- with hyperlipidemia, obesity, and insulin resistance. In
ulation of metabolic genes. In this review, we discuss support of their mutual effects, studies have shown that
recent findings regarding the functions of TH in hepatic
metabolism, the relationship between TH and metabolic
disorders, and the potential therapeutic use of thyromi- Glossary
metics to treat metabolic dysfunction in the liver.
Carbohydrate metabolism: refers to the production, storage, and use of
carbohydrates in cells to maintain energy homeostasis. It is highly conserved
Thyroid hormone and metabolic homeostasis and is essentially glucose metabolism to control blood glucose levels.
Thyroid hormone (TH, see Glossary) mediates important De novo lipogenesis: the process in which acetyl-CoA is converted to FAs,
which are then esterified with glycerol to form TGs that are packaged in VLDLs
physiological processes such as development, growth, and and secreted from the liver.
metabolism [1,2]. Intracellular triiodothyronine (T3) is the Gluconeogenesis: during starvation, glucose is generated from non-carbohy-
active form of TH and binds to the thyroid hormone recep- drate carbon substrates (such as pyruvate, lactate, and FAs) in the liver to
maintain blood glucose levels.
tor (TR), which is a transcription factor that belongs to the Hyperlipidemia: a medical condition characterized by abnormally high levels of
nuclear receptor superfamily (Figure 1). The TR exists in lipid or lipoproteins in the blood.
two isoforms: TRa and TRb. The TRa isoform is highly Hyperthyroidism: a condition in which the thyroid gland produces and secretes
excessive amounts of the free thyroid hormones T3 and/or T4. Graves disease
expressed in the heart, muscle, and adipose tissue, where- is the most common cause of hyperthyroidism.
as TRb is the predominant isoform in the liver [3]. The TR Hypothyroidism: a common endocrine disorder of underactive thyroid or low
acts as a ligand-dependent transcription factor to regulate thyroid, in which the thyroid gland does not produce enough thyroid hormone.
It causes several symptoms including tiredness, cold intolerance, and weight
genes involved in the biological functions of TH (Figure 1) gain.
[4]. Lipid metabolism: refers to the regulation of lipids in cells such as their
TH has profound effects on body weight, thermogenesis, degradation (lipolysis) or formation (lipogenesis). TGs and cholesterol are the
major components of lipid metabolism. TGs are important for energy storage
and lipolysis; these effects are mediated primarily through in adipocytes and muscle cells, whereas cholesterol is a ubiquitous constituent
the action of TH on skeletal muscle and adipose tissue [1]. of cell membranes, steroids, bile acids, and as signaling molecules.
Lipolysis: a highly regulated process of lipid breakdown that involves the
TH can also regulate fatty acid (FA), cholesterol, and
hydrolysis of TGs into glycerol and FAs.
carbohydrate homeostasis through its actions on the liver Lipophagy: the autophagic degradation of cellular lipids, which involves the
(Figure 2) [1]. Thus, thyroid dysfunctions can result in sequestration of lipid droplets and their degradation via lysosomal lipase.
Non-alcoholic fatty liver disease (NAFLD): a condition in which fat accumulates
intrahepatic as well as systemic dysregulation of the me- in the liver independent of alcohol intake. It is generally related to metabolic
tabolism of nutrients that serve as important energy disorders and is one of the major causes for fatty liver. Non-alcoholic
sources for cells and adversely affect hepatic lipid and steatohepatitis is the most extreme form of NAFLD and a major cause of liver
cirrhosis.
carbohydrate metabolism [1]. Nuclear receptor superfamily: a family of transcription factors, most of which
In clinical hypothyroidism, patients gain weight owing to directly bind to DNA in a hormone-dependent manner to regulate gene
a decreased basal metabolic rate, particularly in muscle and expression.
b-Oxidation: a multi-step process of FA breakdown to form acetyl-CoA in the
brown fat [1]. Additionally, hypothyroidism is associated mitochondrial matrix, which subsequently enters into the tricarboxylic acid
cycle.
Corresponding author: Yen, P.M. (paul.yen@duke-nus.edu.sg). Reverse cholesterol transport (RCT): a process resulting in the net movement
Keywords: thyroid hormone; lipid metabolism; glucose metabolism; liver. of cholesterol from peripheral tissues back to the liver via the plasma
*
Sinha, R.A. and Singh, B.K. contributed equally to this review compartment.
Thyroid hormone (TH): includes thyroxin (T4) and triiodothyronine (T3). T3 is a
1043-2760/
ligand for TRs, which modulate cell proliferation, development, and metabo-
2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tem.2014.07.001
lism. TH is produced by the thyroid gland.

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Review Trends in Endocrinology and Metabolism xxx xxxx, Vol. xxx, No. x

T4 T3
S
(i) ACC1, LPOT14, FAS
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Lipogenesis hREB
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resistance
T3 synthesis +

T3
T3
HATs TRENDS in Endocrinology & Metabolism
Histone Gene
CoAct
+ T3 RXR TR
T3 acetylaon
Figure 2. Thyroid hormone regulation of fatty acid, cholesterol, and glucose
TRE
Transcriponal acvaon metabolism. (i) Thyroid hormone (T3) may increase fatty acid (FA) uptake in the
Nucleus liver via the regulation of FA transporter proteins such as FA translocase (FAT; also
HDACs Histone known as CD36). T3 is known to increase hepatic lipogenesis by upregulating
NCoR
T3 RXR TR
deacetylaon
proteins including Spot14, FA synthase (FAS), acetyl-CoA carboxylase 1 (ACC1),
TRE G
Gene liver X receptor (LXR), carbohydrate-responsive element-binding protein
(CHREBP), and malic enzyme (ME). Activation of hepatic lipases and lipophagy
Transcriponal repression
has been implicated in the intrahepatic lipolysis induced by T3. FAs released via
lipolysis are shuttled into hepatic mitochondria for oxidation; this process is
positively regulated via the T3 induction of carnitine palmitoyltransferase-1 (CPT-
1), sirtuin 1 (SirT1), peroxisome proliferator-activated receptor gamma, coactivator
TRENDS in Endocrinology & Metabolism
1 alpha (PGC1a) and fibroblast growth factor-21 (FGF-21). (ii) Cholesterol uptake
via low-density lipoprotein receptor (LDL-R) endocytosis is promoted by T3. Other
Figure 1. Thyroid hormone signaling. Thyroxine (T4), the precursor of 3,5,30 -
proteins involved in cholesterol uptake, such as sterol regulatory element-binding
triiodothyronine (T3), or T3 enters the cytoplasm via various thyroid hormone (TH)
protein-1c (SREBP-2) and scavenger receptor class B1 (SR-B1), are also induced by
transporters (e.g., MCT8, MCT10, and OATP1C1). The activation and inactivation of
T3. Key genes involved in cholesterol turnover and bile production, such as
TH occur through iodothyronine deiodinases (Dio1, Dio2, and Dio3), which constitute
cytochrome P450 7A1 (Cyp7A1; also known as cholesterol 7-alpha-
a subfamily of deiodinase enzymes. Dio1 and Dio2 convert prohormone thyroxine
monooxygenase) and ATP-binding cassette sub-family G member 8 (ABCG5/8),
(T4) to the active hormone triiodothyronine (T3). Inactivation of TH occurs through
are also induced by T3 to increase net reverse cholesterol transport. (iii) T3 bound
Dio3, which converts T4 to the inactive reverse triiodothyronine (rT3) or converts
thyroid receptor (TR) directly upregulate TR target genes and key gluconeogenic
active T3 to the inactive diiodothyronine (T2). Active T3 enters the nucleus and binds
enzymes such as phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6-
to TH receptors (TRs), resulting in the recruitment of co-activator complexes (Co-Act)
phosphatase (G6PC) in the liver. Increased deacetylation and activation of the
with histone acetyl transferase (HAT) activity. The HAT activity of Co-Act increases
master gluconeogenic transcription factor forkhead box O1 (FoxO1) by SirT1 is
acetylation of histone protein tails, thus creating a permissive chromatin
also modulated by T3 to increase gluconeogenesis. Apart from regulating
environment, near TREs on the target gene, and promoting gene transcription. T3
gluconeogenic gene transcription, increased alanine transport and inhibition of
trans-activates the expression of genes in nearly every vertebrate cell. TRs, in the
insulin signaling may also contribute to TH-induced hepatic glucose production. +
absence of T3, recruit nuclear co-repressor complexes (NCo-R) with histone
indicates positively regulated.
deacetylase activity (HDAC), which ultimately repress target gene transcription.
Abbreviations: RXR, retinoid X receptor; TRE, thyroid hormone response element;
MCT8, monocarboxylate transporter 8; MCT10, monocarboxylate transporter 10;
OATP1C1, organic anion-transporting polypeptide 1c1.

key target genes of TH are downregulated in fatty livers of tissue [11]. In the hyperthyroid state, excessive hepatic
morbidly obese patients undergoing bariatric surgery [8]. lipid oxidation and oxidative phosphorylation can generate
Hypothyroid patients also commonly have hypercholes- reactive oxygen species that cause hepatic tissue damage
terolemia due to decreased hepatic low-density lipoprotein [12]. Indeed, hepatitis and liver failure have been reported
receptor (LDL-R) expression, which leads to an im- to occur in uncontrolled and/or prolonged hyperthyroidism
pairment in cholesterol uptake [9]. This, in turn, leads [13]. Additionally, hyperthyroidism can induce gluconeo-
to a decrease in cholesterol turnover and excretion, and a genesis and glycogenolysis. It is a well-known clinical
marked increase in serum apolipoprotein B (ApoB) [10], phenomenon that hyperthyroidism can induce hyperglyce-
total cholesterol, and LDL cholesterol levels. A decrease in mia as well as worsen glycemic control in diabetic patients
the clearance of triglycerides (TGs) from plasma and an [14].
accumulation of intermediate LDL particles has also been With the advent of new molecular biological methods,
observed in hypothyroid patients [10]. knockout and knock-in mouse models, and metabolic char-
In hyperthyroidism, the basal metabolic rate of patients acterization of different physiological and genetic states,
is increased and often accompanied by weight loss when we are beginning to gain a much deeper understanding of
caloric intake cannot keep pace with increased energy TH actions on liver metabolism. In this review, we describe
consumption [11]. However, serum total cholesterol and the molecular and intracellular mechanisms utilized
TG levels are decreased owing to increased clearance via by TH that impact the hepatic regulation of lipids and
the reverse cholesterol transport (RCT) pathway and he- carbohydrates in normal and pathological conditions.
patic b-oxidation is increased due to lipolysis from adipose These findings not only enhance our understanding of liver
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dysfunction associated with metabolic syndrome, but may result suggests that, at least in these mouse models,
also provide new tools for the diagnoses and treatment of dominant negative TRb and TRa1 may act on different
NAFLD and related disorders. repertoires of genes with contrasting effects on hepatic
lipid metabolism [28].
TH regulation of hepatic FA uptake
Circulating free FAs (FFAs) generated through the lipoly- TH regulation of hepatic lipolysis and b-oxidation
sis of adipose TG stores are an important source of lipid for Although TH can stimulate lipogenesis, prolonged treat-
the liver. FFAs are taken up by hepatocytes via protein ment leads to increased FA oxidation [29]. However, the
transporters such as fatty acid transporter proteins mechanism for this switch is currently unknown. Most of
(FATPs), liver FA binding proteins (L-FABPs), and FA the FAs used for oxidation are derived from FFAs from
translocase (FAT; also known as CD36). Studies have adipose tissue via TH-mediated lipolysis. FAs are also
shown that knockdown of FATP2 and FATP5 protected released from TG stores during hepatic lipolysis. Lipases
against high fat diet-induced hepatosteatosis. Knock down hydrolyze lipids to form FAs and glycerol. TH does not
of FATP5 also partitioned lipids towards skeletal muscle seem to significantly alter the gene or protein expression of
and heart, and away from the liver [15]. Similarly, upre- classic lipases in the liver, with the exception of hepatic
gulation of FAT in the livers of lean mice increased hepatic lipase, which is transcriptionally upregulated by TH [30].
FA uptake, TG storage, and secretion. [16]. Additionally, The effect of TH on adipose TG lipase in liver is presently
L-FABP knockout mice were resistant to diet-induced unclear. TH can also increase the gene expression of zinc-
hepatic TG accumulation [17,18]. Although FA transpor- a2-glycoprotein, a protein that contributes to lipolysis in
ters are transcriptionally induced by peroxisome prolifera- hepatocytes [31]. Although it is not known whether hepatic
tor-activated receptors (PPARs) [19], recent data suggest lipases and zinc-a2-glycoprotein are direct targets of TR,
that FA transporters may also be regulated by TRs. Using these findings shed light on a relatively less-studied aspect
radiolabeled FA infusion techniques, it was shown that of hepatic lipid hydrolysis, which might have a crucial role
FA uptake from TG-rich lipoproteins was increased by TH in both normal and diseased conditions [32].
in a tissue-specific manner [19]. Hyperthyroidism also Recent studies have shown that autophagy is a key
increased TG-derived FA uptake in all oxidative tissues process in hepatic lipolysis and lipid droplet degradation
except brown adipose tissue, whereas hypothyroidism [33]. The resultant FFAs released after hydrolysis are
increased TG-derived FA uptake in lipid-storing white catabolized by b-oxidation within nearby mitochondria.
adipose tissue and decreased its uptake in liver [20]. Moreover, TH was shown to increase lipophagy, a specific
Moreover, hepatic FAT expression was suppressed in ani- autophagic process used to traffic lipids to the lysosome, in
mal models of postnatal hypothyroidism [21]. Although hepatocytes [34]. In particular, TH significantly increased
these studies indicate that TH may be important in regu- the number of lipid-laden autophagosomes and lysosomes
lating FA uptake in different tissues such as the liver, the in both human hepatic cells and mouse liver. Although the
precise mechanism by which TH alters FATP activities precise mechanism used by TH to induce hepatic lipophagy
needs further investigation. is not well understood, it is TR-dependent [33]. Addition-
ally, blockade of autophagic flux in cell culture [34] and in
TH regulation of hepatic lipogenesis vivo significantly reduced TH-induced ketogenesis, which
The synthesis of FFA from acetyl-CoA (de novo lipogenesis) is the final step in b-oxidation. Collectively, these findings
is regulated through various nuclear hormone receptors, suggest that lipophagy is a major mechanism for supplying
including liver X receptor (LXR), PPAR, and TR. TH FFAs for b-oxidation by TH [34]. Moreover, loss of lipo-
regulates hepatic lipogenesis by stimulating the transcrip- phagy in TRbPV mice correlated with a diminished b-
tion of three key lipogenic transcription factors that are oxidation capacity and hepatosteatosis [27,34]. Thus, a
known to regulate the expression of genes involved in decrease in lipophagy due to decreased intracellular TH
lipogenesis: sterol regulatory element-binding protein-1c levels or TH action may contribute to hepatosteatosis.
(SREBP-1c) [22], LXR [23], and carbohydrate-responsive Oxidation of FAs to acetyl-CoA occurs within mitochon-
element-binding protein (CHREBP) [24]. TH can also di- dria, peroxisomes, and the endoplasmic reticulum. FAs are
rectly increase the transcription of lipogenic enzymes such activated by acyl-CoA-synthetase to acyl-CoA in the cyto-
as acetyl-CoA carboxylase (ACC), malic enzyme (ME), fatty sol. This process is essential for enabling FAs to cross
acid synthase (FAS), and Spot14 (S14) [25]. Liganded TR membranes and enter organelles. Short (aliphatic tails
associates with co-activator complex on TH response ele- of fewer than six carbons in length) and medium-chain
ments (TREs) in the promoter region of these genes to FAs (aliphatic tails of 612 carbons in length) pass the
enhance transcription. However, contrary to its positive mitochondrial membrane without activation, whereas ac-
regulation of most of the lipogenic genes, TH negatively tivated long-chain FAs are shuttled across the membrane
regulates stearoyl-CoA desaturase-1 (SCD-1) via a TRE- by carnitine palmitoyltransferase-1 (CPT-1) [35]. The gene
independent mechanism in mice [26]. Distinct abnormali- expression of CPT-1 and pyruvate dehydrogenase lipoa-
ties in hepatic lipid metabolism in the PV mutant mouse mide kinase isozyme 4 (PDK4), which leads to decreased
model, which mimics a TR mutation in patients with glycolysis by phosphorylating pyruvate dehydrogenase,
resistance to TH, have also been reported [27]. Interest- are positively regulated by TH. Recently, TR was shown
ingly, whereas livers from TRbPV mice had markedly to assemble with the histone deacetylase SirT1 and perox-
increased lipid accumulation, liver mass and lipogenic isome proliferator-activated receptor gamma coactivator
gene expression were decreased in TRaPV mice. This 1a (PGC-1a) on the TREs of their promoters [36]. SirT1 is
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crucial for maintaining normal hepatic lipid and glucose receptors through their mutual competition for a limited
metabolism [37]. TH-bound TR can also increase the pool of nuclear RXRs [25]. Hashimoto and Mori [50] dem-
expression of fibroblast growth factor-21 (FGF21) in a onstrated that the D337T TRb mutation, which diminishes
PPARa-dependent manner [38]; FGF21 is a pivotal regu- TRRXR heterodimerization, promoted RXR interaction
lator of mitochondrial activity and b-oxidation in the liver with LXR and induced the hypocholesterolemic effects of
[39]. However, more recent findings suggest that FGF21 LXR. Similarly, the dominant-negative TRa P398H muta-
levels may be regulated independent of TH action in vivo tion, which still enables the mutated TR to heterodimerize
[40]. Finally, in addition to increasing substrate availabili- with RXR, interfered with PPARa signaling and activation
ty through increased lipolysis and CPT-1 expression, TH of its target genes to impair b-oxidation [51]. Interestingly,
also increases the biogenesis of hepatic mitochondria by LXRRXR dimers negatively regulated TH signaling by
stimulating PGC-1a expression [41]. Collectively, these downregulating the expression of hepatic deiodinase 2 [52].
findings suggest that TH strongly induces coordinated Apart from competition among nuclear receptors to form
lipid catabolism by stimulating lipophagy-mediated lipol- heterodimers with RXR, there can also be competition for
ysis and mitochondrial b-oxidation of FA. binding to common DNA response elements. In this regard,
transcription of the ATP-binding cassette transporter A1
TH and regulation of cholesterol homeostasis (A1), which is involved in cholesterol efflux from cells, is
Normal serum levels of TH are essential for maintaining a reciprocally regulated by the competitive binding of TR and
sufficient pool of cholesterol to meet the bodys require- LXR to a common direct repeat 4 (DR4) element located on
ments as well as for regulating the crucial steps of choles- its promoter [50]. Besides other nuclear receptors, direct
terol synthesis, uptake, and metabolism [1]. TH regulates interaction with nuclear co-repressors, such as silencing
serum cholesterol levels by stimulating its hepatic synthe- mediator for retinoid and thyroid hormone receptors
sis, serum uptake, and intrahepatic conversion to bile (SMRT) [53] and nuclear receptor co-repressor (NCoR)
acids. TH modestly induces 3-hydroxy-3-methyl-glutaryl [34,54,55], can also regulate hepatic lipid and cholesterol
coenzyme A (HMG CoA) reductase and farnesyl pyrophos- metabolism and potentially modify TH signaling. More-
phate gene expression to promote cholesterol synthesis over, distinct isoform-specific effects of TR were also at-
[42]. However, TH strongly induces the gene and protein tributed to have selective affinity to NCoR [28]. Thus,
expressions of LDL-R and ApoA1, which increase choles- competition among nuclear receptors for RXR, common
terol uptake into the liver [43]. By contrast, patients with DNA sites, and co-repressors and/or co-activators, enables
hypothyroidism typically have hypercholesterolemia and intricate crosstalk between nuclear receptor signaling
LDL accumulation in the liver, which can be normalized pathways.
after TH replacement [9]. Apart from direct stimulation by
TH, the LDL-R gene is subject to regulation by SREBP-2, Regulation of hepatic lipid metabolism via non-classical
which, in turn, is directly regulated by TH [44]. Addition- TH signaling
ally, the transcription of LDL-R-related protein 1 (LRP-1), Although most actions of TH are mediated by transcrip-
a lipoprotein involved in the removal of chylomicron rem- tional regulation through nuclear TRs, there is evidence for
nants and very LDL (VLDL), is increased by TH [45]. a non-classical TH signaling pathway that does not require
Recently, other LDL-R-independent mechanisms, such nuclear TRs [56]. The lipid-lowering effect of TH on FaO
as increased expression of cholesterol 7a-hydroxylase rat hepatoma cells, which are devoid of TRs, engages a non-
(Cyp7A1), the rate-limiting enzyme in the synthesis of bile receptor-mediated mechanism involving both short-term
acid from cholesterol, or decreased ApoB protein levels, stimulation of mitochondrial O2 consumption and long-
have been proposed to explain the TH-mediated reduction term transcriptional effects on PPARs [57]. Additionally,
of LDL [46,47]. Furthermore, TH-induced secretion of in contrast to its suppressive effect on mouse SREBP-1c,
cholesterol into bile acids is dependent on TH stimulation TH appears to upregulate the human homolog via a non-
of ATP-binding cassette transporter G5/G8 (ABCG5/G8) genomic ERK-mediated pathway in HepG2 cells [58]. TH
complex gene transcription [48]. Finally, in addition to the also increases b-oxidation in HeLa cells through a mecha-
transcriptional regulation of genes involved in cholesterol nism that involves an increase in cytosolic calcium and
synthesis and bile secretion, TH may also utilize miRNAs activation of 50 AMP-activated protein kinase (AMPK) [59].
to regulate these processes. Recently, miRNA-181d was A deeper mechanistic understanding of non-genomic TH
shown to decrease the expression of caudal type homeobox signaling may help explain some of the acute effects of TH
2 (cdx2), a regulator of sterol O-acyltransferase 2 (Soat2), a on hepatic lipid and mitochondrial metabolism, which have
gene that is crucial for the hepatic secretion of cholesterol remained elusive so far.
esters; this may represent a novel mechanism for TH to
lower serum cholesterol [49]. TH regulation of hepatic carbohydrate metabolism
Although the role of TH in carbohydrate metabolism has
Crosstalk of TR-mediated hepatic lipid metabolism with been studied for nearly a century, the molecular and
other nuclear receptor signaling pathways intracellular mechanisms of its regulation have only re-
TR often forms heterodimers with retinoid X receptors cently begun to be understood. Clinically, hyperthyroidism
(RXRs) to regulate target gene expression. However, be- is associated with increased glucose production, absorp-
cause RXRs also heterodimerize with several other nuclear tion, and utilization, whereas hypothyroidism is charac-
receptors, such as PPAR and LXR, TR heterodimerization terized by decreased glucose utilization by peripheral
with RXR can influence gene regulation by other nuclear tissues [1]. TH influences glucose metabolism peripherally
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through its actions on many organs, particularly the pan- Isoform-and liver-specific TH analogs
creas, muscle, adipose tissue, and the liver [60]. TH can As mentioned earlier, the tissue-specific distribution of TR
also act centrally to modulate hepatic glucose production isoforms, TRa and TRb, provides a therapeutic opportuni-
and insulin sensitivity via a sympathetic pathway connect- ty for selective TH action in specific tissues such as the liver
ing the paraventricular hypothalamus to the liver, without [71]. In particular, liver-selective or TRb-specific agonists
any changes in circulating glucoregulatory hormone levels can uncouple the beneficial effect of TH on hepatic and
[61,62]. plasma lipids from its deleterious effects on heart and
Hyperthyroidism is known to stimulate hepatic gluco- bone. In this regard, selective thyroid receptor modulators
neogenesis by increasing alanine transport and its conver- could potentially be used to treat major metabolic disor-
sion to glucose. TH also directly increases the expression of ders such as obesity, NAFLD, hypercholesterolemia, and
both the rate-limiting enzyme in gluconeogenesis, phos- T2DM [7274]. For example, treatment of leptin-deficient
phoenolpyruvate carboxykinase (PCK1) [63], and glucose- ob/ob mice with a TRb-selective agonist reduced plasma
6-phosphatase (G6PC) [64]. The TH analog GC-1 can acti- glucose and improved insulin resistance [25,73,74]. A liver-
vate transcription of these gluconeogenic genes [25]. Re- selective pro-drug that is metabolized into a TH mimetic
cently, several groups studied the effect of TH on hepatic within the liver was also effective in lowering serum
glucose production in more detail. It was shown that SirT1 cholesterol and TG levels [75], suggesting that activating
contributes to TH regulation of CPT-1, the acyl-CoA carrier TR specifically in the liver may be a therapeutic approach
protein that is important for b-oxidation of FAs [36,64]. towards improving lipid profiles.
SirT1 interacts with liganded TRb1 in vitro to promote its
deacetylation and activation while enhancing ubiquitin- TH analogs, hypercholesterolemia, and RCT
dependent TRb1 turnover. which is a common response of TH can decrease serum cholesterol levels in animals and
nuclear receptors (NRs) to ligand binding [36,64]. Similar- humans, particularly in combination with statin therapy
ly, it was recently reported that FoxO1 is crucial for the [76,77]. The primary mechanism for this beneficial effect is
TH-mediated transcription of PCK1 and G6PC [65]. the enhancement of reverse cholesterol transport (RCT).
In vivo, FoxO1 siRNA knockdown markedly decreased Studies in rodents showed that TH and the thyromimetic
the TH-mediated transcription of gluconeogenic genes in compound CGS-23425 increased the plasma levels of
mice [65]. TH also was unable to induce FoxO1 deacetyla- ApoA1 [78], suggesting that TH may promote the synthesis
tion or hepatic PCK1 gene expression in TRb-null (TRb/) of high-density lipoprotein (HDL) and influence the initial
mice [65], suggesting that SirT1 deacetylation and activa- step of RCT. Additionally, TH and thyromimetics in-
tion of FoxO1 were TR-dependent. Collectively, these creased RCT by increasing the expression and activities
results raise the possibility that drugs targeting the SirT1 of several key proteins involved in cholesterol metabolism,
pathway in the liver may also modulate TH regulation of including the following: scavenger receptor class B member
hepatic target genes involved in lipid and carbohydrate 1 (SRB1), which is responsible for the uptake of cholesterol-
metabolism. enriched HDL; CYP7A1, which converts cholesterol into
bile acids in the liver; and ABCG5/G8, which promotes
TH and hepatic insulin resistance biliary cholesterol excretion [75,7982]. One of the first
Glucose homeostasis in humans is regulated by insulin chemically synthesized TH analogs was 3,5-diiodothyro-
secretion from pancreatic b-cells and glucose metabolism propionic acid (DITPA). Although beneficial effects were
by insulin-sensitive tissues such as the liver and muscle noted on cholesterol and weight, DITPA resulted in in-
[66]. Insulin facilitates glucose utilization in peripheral creased serum markers of bone turnover, suggesting that
tissues and suppresses hepatic glucose production (HGP). DITPA has a negative effect on bone [83]. Moreover, cho-
Insulin resistance is often associated with obesity and lesterol-independent positive effects of thyromimetics have
predisposes affected individuals to glucose intolerance been observed in rodent models of atherosclerosis [84].
and T2DM [67]. Clinically, hyperthyroidism is associated
with impaired glucose tolerance, hepatic insulin resis- TH analogs and hepatic carbohydrate metabolism
tance, and increased HGP [14,25]. TRb-specific analogs have favorable effects on lipid metab-
One major connection between glucose metabolism and olism; however, it appears that TRa may have some oppo-
TR signaling is the stimulation of ChREBP by TH, a basic site actions to TRb with respect to metabolism. In contrast
helixloophelix leucine zipper transcription factor that to TRbKO and TRbPV knock-in mice, which have in-
stimulates the expression of enzymes promoting lipogene- creased hepatosteatosis, TRa knockout (Tra-null) mice
sis in response to glucose and insulin [68]. Thus, TH can were protected from hepatosteatosis and high fat diet-
potentiate inappropriate HGP during insulin resistance as induced hepatic insulin resistance [85]. Thra-0/0 mice were
well as stimulate lipogenesis during hyperinsulinemia. also leaner, less sensitive to high fat diet-induced obesity,
The overall effects of TH on glucose tolerance and insulin and had significantly decreased liver TG and cytosolic
sensitivity are complex and mixed [14,37,69,70], and some diacylglycerol levels. Along with these changes, insulin-
of its actions on other tissues may counteract, in part, the stimulated p-Akt/Akt ratios were also increased in these
insulin resistance and glucose intolerance in the liver. For mice compared with wild-type mice. Interestingly, a simi-
example, TH reduces body fat and increases mitochondrial lar phenotype was observed in TRaPV knock-in mice when
oxidative metabolism in skeletal muscle, which can in- compared with TRbPV knock-in mice [86]. Collectively,
crease insulin sensitivity and glucose utilization while it these findings suggest that development of a TRa antago-
promotes HGP [25]. nist may have therapeutic potential. However, it should be
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noted that knock-in mice expressing another mutant TRa


Box 1. Outstanding questions
with a decreased binding affinity for TH exhibited de-
creased metabolic rates and increased visceral fat [87].  What is the mechanism(s) by which TH activates SIRT1 to regulate
These finding raise the interesting possibility that specific lipid and glucose homeostasis?
 What is the role of miRNAs in the TH regulation of hepatic lipid
TRa mutations may have variable effects on the metabolic and carbohydrate metabolism?
phenotype. Notably, patients with TRa mutations have  How does TH signaling crosstalk with hepatic insulin signaling
recently been identified, and these patients show increased and how does it contribute to insulin resistance?
body mass index values and decreased metabolic rates  Is there intrahepatic TH resistance that triggers fatty liver
[88,89]. development?
In addition to TR isoform-specific or liver-specific ana-
logs, TH metabolites may also have beneficial effects on signaling pathways, and transcription factor crosstalk that
hepatic metabolism. Recently, the diiodothyronine (T2) are affected by TH regulation of carbohydrate and lipid
mimetic TRC150094 was developed for the treatment of metabolism in normal and pathological conditions. Given
heart failure, dyslipidemia, and diabetes. As TRC150094 the global rise of metabolic disease, a better understanding
has very low affinity for both TRa and TRb isoforms, it is of the physiological, metabolic, and molecular relation-
thought to enhance the mitochondrial oxidative capacity in ships between TH action and metabolism may lead to
liver via the increased activity of complex V [74]. The improved therapies for these diseases. Indeed, future stud-
development and use of TR-independent analogs opens ies in these areas (Box 1) may help determine whether
new avenues for the treatment of metabolic disorders NAFLD, insulin resistance, and dyslipidemia in subclini-
through their non-genomic actions. cal hypothyroidism, or hyperglycemia in subclinical hyper-
thyroidism, warrant correction of serum or intrahepatic
TH and analogs in treating NAFLD TH levels. Intrahepatic TH levels could potentially be
NAFLD is a major global health problem that is associated assessed by measuring serum protein and metabolomic
with obesity and insulin resistance [90]. Its pathogenesis markers. Finally, a better understanding of TH action and
remains poorly understood, and, currently, there are no hepatic metabolism may also lead to the development of
approved drug therapies [91]. As mentioned earlier, there new and safe thyromimetics that could be beneficial for the
exists a strong association between hypothyroidism and treatment of metabolic conditions such as hyperlipidemia,
NAFLD [7,92]. This association seems plausible because NAFLD, T2DM, and obesity.
clinical thyroid dysfunction can lead to hyperlipidemia,
obesity, and insulin resistance, all of which are major Acknowledgments
components of metabolic syndrome [93] and are implicated This manuscript was supported by grant NMRC/CIRG/1340/2012 to
in the pathogenesis of NAFLD. In human NAFLD micro- P.M.Y. from the National Medical Research Council, Singapore.
array studies, hepatic lipid accumulation caused the down-
regulation of a set of TH-responsive genes, including some References
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