Introduction
Excessive lipid buildup in liver cells often leads to nonalcoholic fatty liver
disease (NAFLD), which is typically associated with obesity, dyslipidemia, and
insulin resistance, which are the main features of metabolic syndrome (MetS) [1]. Presently, NAFLD is the primary factor
behind chronic liver disease on a global scale, impacting around a quarter of the
overall populace [2]. Lately, alterations in
different endocrine organs, such as the thyroid [low thyroid function and a
decreased proportion of thyroxine (T4) to triiodothyronine (T3)], skeletal muscle
(sarcopenia), and the pancreas [type 2 diabetes (T2DM)], have been linked to NAFLD
[3]
[4].
Thyroid hormones (THs) play a crucial role in numerous physiological functions,
encompassing the regulation of lipid, carbohydrate, and protein metabolism, and the
preservation of thermal balance. They are essential for cellular development,
growth, maturation, and mitochondrial energy metabolism. Consequently, TH signaling
impacts nearly every organ, with the liver being among the most vital targets of THs
and skeletal muscle also being an important target organ for THs [5]
[6].
Thyroid dysfunction can have adverse effects on hepatic lipid and carbohydrate
metabolism, and also affects the regulation of muscle fibers. It has been reported
that serum levels of TT3 in the euthyroid elderly subjects were positively
associated with muscle strength and negatively association with the risk of
sarcopenia, a complication of many chronic diseases [6]. Lately, there has been a growing focus on the connection between
hypothyroidism and NAFLD due to their shared characteristics of hyperlipidemia,
obesity, and insulin resistance [5].
This review explores the connections between thyroid dysfunction, particularly
hypothyroidism, and NAFLD, and the functions of THs and thyroid-stimulating hormone
(TSH) in the pathophysiology of NAFLD. Furthermore, it examines new and potentially
beneficial therapeutic options for addressing NAFLD induced by TH imbalances. Above
all, our main goal is to motivate healthcare professionals to acknowledge the
importance of focusing on THs as a potential strategy for managing NAFLD.
Thyroid malfunction and NAFLD patients: Clinical studies
Hypothyroidism, a prevalent hormonal disorder, is identified by an insufficiency
of THs [7]. Primary overt hypothyroidism,
as defined traditionally, is marked by an elevated plasma TSH level beyond the
normal range and a below-normal concentration of free thyroxine (FT4),
accompanied by clinical symptoms. In contrast, subclinical hypothyroidism is
characterized by a plasma TSH level that exceeds the normal range, while plasma
TH levels remain within the normal range and there are no apparent clinical
symptoms [7]. The earlier mention of THs
and TSH emphasizes their significant contributions to maintaining energy and
metabolic balance, prompting the inquiry about a possible association between
thyroid disorders and NAFLD. A sum of 9419 eligible participants with baseline
thyroid function measurements and NAFLD data were included in the Rotterdam
study, which was a comprehensive study of a large population-based cohort. The
fatty liver index at baseline or ultrasound at follow-up was used to assess
NAFLD. The study conducted by Bano et al. [8] revealed a significant correlation between both subclinical and
overt hypothyroidism and a higher likelihood of NAFLD. Despite controlling for
variables such as age, gender, body mass index (BMI), duration of follow-up, and
cardiovascular risk factors like smoking, lipid profile, hypertension, and
diabetes, this correlation remained consistent. Conversely, elevated levels of
plasma FT4 were linked to a decreased likelihood of developing NAFLD. Consistent
with this discovery, a survey conducted on 878 euthyroid elderly Chinese
participants demonstrated that the levels of FT4 in the blood, even when falling
within the normal range, were linked to the likelihood of NAFLD in this specific
group [9]. A study [10] discovered that reduced levels of serum
total T4 (TT4) were strongly linked to a higher chance of developing NAFLD, this
connection remained significant even when accounting for age or BMI. Moreover,
patients with NAFLD who had low FT3 levels were found to have a strong
correlation with a high NAFLD fibrosis score and liver stiffness [11]. Furthermore, Mantovani et al.
conducted a recent systematic review and meta-analysis [12], consisting of 12 cross-sectional
studies, 3 longitudinal studies, and a participant pool of 44 140 individuals,
the findings of which revealed a notable correlation between hypothyroidism and
the occurrence as well as the extent of NAFLD. Besides, TSH has been recognized
as a standalone risk element for NAFLD and hepatic fibrosis. Moreover, elevated
TSH concentrations within the normal range have been associated with NAFLD,
irrespective of TH concentrations and metabolic risk factors [13]
[14]. Bril et al. conducted research [15] on 232 individuals diagnosed with T2DM in the United States as
part of a cross-sectional study and it was noted that a decline in FT4 levels in
the blood was linked to a higher likelihood of NAFLD and greater amount of
triglycerides within the liver, measured through MRS. Nevertheless, there was no
correlation observed between decreased plasma FT4 concentrations and the
presence of more advanced histological characteristics of NAFLD (such as
inflammation, ballooning, or fibrosis) among a subgroup of individuals who
underwent liver biopsy. Moreover, in a study that looked back over a period of 4
years and included 18 544 individuals from Korea, Lee et al. [16] found that there was no association
between either subclinical or overt hypothyroidism and a higher likelihood of
developing NAFLD, which was verified by means of abdominal ultrasonography. This
lack of association held true independently of certain metabolic
confounders.
The causal connection between primary (both subclinical and overt) hypothyroidism
and the risk of developing NAFLD independently of coexisting cardio-metabolic
risk factors has not been proven by these observational studies. The
contradictory results in these observational studies can be ascribed to notable
discrepancies in the design of the studies, attributes of the study sample
(including variables such as diet, race, and exercise), and the standards
employed for identifying hypothyroidism and NAFLD. Even with the publication of
meta-analyses [12]
[17]
[18]
[19], divergent outcomes are
possible due to differences in the criteria for including and excluding studies
and using distinct statistical methods. Hence, it is crucial to conduct thorough
and well-planned prospective cohort studies that utilize consistent diagnostic
standards for both hypothyroidism and NAFLD. These studies aim to determine any
potential cause-and-effect connection between hypothyroidism and the likelihood
of developing NAFLD.
The role of THs and TSH in NAFLD
THs production and action
T4 and T3, which are the primary THs, are hormones derived from amino acids.
The hypothalamic-pituitary-thyroid (HPT) axis controls the manufacturing and
release of THs. On the other hand, THs act on the pituitary gland and
hypothalamus to suppress the production of TSH, creating a feedback loop
that operates in a negative manner within the HPT axis. T4 is mainly
produced by the thyroid gland, whereas the conversion of T4 into the
powerful active form of THs, T3, occurs in peripheral tissues through the
action of iodothyronine deiodinases (DIO) [20].
Traditionally, THs function as ligands for thyroid hormone receptor (TR) α
and TRβ, which are produced by the THRA and THRB genes, respectively. TRs
belong to the nuclear receptor superfamily. In order to produce genomic
effects, TRs have the ability to create heterodimers with the retinoid X
receptor (RXR), which then attach to thyroid hormone response element (TRE)
located in the promoter regions of genes regulated by TH/TR [21]. Significantly, TRs control
subsequent objectives regardless of the presence or absence of THs. When THs
are not present, nuclear receptor corepressor (NCoR) and its counterpart,
silencing mediator of retinoid and thyroid hormone receptors, function as
corepressors. Recruitment occurs when they form TR-RXR heterodimers that are
bound to the TRE, resulting in the suppression of basal transcriptional
activity. Moreover, THs cause structural alterations in TRs, leading to the
liberation of corepressors and the recruitment of coactivators such as
steroid receptor coactivator and CREB-binding protein/p300. These changes in
chromatin structure facilitate the transcriptional activation of target
genes [21]. The main active ligand for
TRs is T3 due to its approximately 10 times higher affinity compared to T4
[22]. In addition, THs can also
activate the MAPK/ERK 1/2 and phosphatidylinositol-3-kinase (PI3K)/AKT
pathways by binding to the cell surface integrin αvβ3 receptor, acting
independently of TRs [23].
Thyroid hormone-mediated regulation of lipid metabolism and mitochondrial
activity in the context of NAFLD
THs enhance the utilization of glucose and lipids, leading to elevated oxygen
consumption and breakdown of energy stores in various organs including
adipose tissue, skeletal muscle, and liver. The effects of THs on the liver
are achieved through the activation of TRβ, which is primarily abundant in
the liver [3]. THs regulate various
aspects of lipid metabolism. Inducing carbohydrate regulatory
element-binding protein (ChREBP), they increase the expression of hepatic
lipogenic genes such as fatty acid synthase (FAS), acetyl-CoA carboxylase
(ACC), and TH-responsive Spot14 homologue (Thrsp; also known as Spot14),
which is a crucial factor in regulating glucose-induced lipogenesis in the
liver [24]. In addition, these also
regulate the transcription of two additional important hepatic lipogenic
transcription factors, namely sterol regulatory element-binding protein-1c
(SREBP-1c) and liver X receptor (LXR), both of which promote the expression
of ACC, FAS, and stearoyl-CoA desaturase-1 (SCD1) [25]
[26]. Surprisingly, THs suppress human SCD1 gene expression in a
TRE-independent manner [27]. THs have
the ability to directly control the transcriptional regulation of hepatic
lipogenic genes, such as FAS, ACC, malic enzyme, and Spot14 [28]. Moreover, THs enhance triglyceride
synthesis by upregulating the levels of fatty acid translocase (FAT, also
referred to as CD36) and fatty acid-binding protein (FABP), facilitating the
entry and uptake of fatty acids [28].
Therefore, rats that had postnatal hypothyroidism exhibited a decrease in
the expression of hepatic FABP and FAT genes, which are associated with the
uptake of fatty acids [29]. Certain
animal studies have shown that thyrotoxicosis enhances the uptake of fatty
acids derived from triglycerides in the muscles and heart, while having
minimal impact on white adipose tissue. Conversely, it reduces this uptake
in brown adipose tissue. On the other hand, in lipid-storing white adipose
tissue, hypothyroidism leads to an increase in the uptake of fatty acids
derived from triglycerides. This increase is linked to higher activity of
lipoprotein lipase. However, in the liver, hypothyroidism has the opposite
effect, causing a decrease in fatty acid uptake [30]. Furthermore, THs impact the
catabolism of liver fats by enhancing the hydrolysis of triglycerides via
adipose triglyceride lipase and hepatic lipase, as well as by stimulating
the production of zinc-α2-glycoprotein in hepatic cells in a manner that
depends on the dosage. This protein contributes to the lipolytic action of
THs [28]. In addition, they enhance
the oxidation of fatty acids by controlling the activation of the carnitine
palmitoyl transferase (CPT)-1α gene in the liver. This can occur through
either a mechanism dependent on peroxisome proliferator-activated receptor-α
(PPARα) signaling or by directly influencing the expression of the CPT-1α
gene [20]. Additionally, the enzymes
of β-oxidation such as Medium-Chain Acyl-CoA Dehydrogenase, Pyruvate
Dehydrogenase Kinase isoform 4, and mitochondrial Uncoupling Protein 2 are
also induced by THs [3]. Mice with
congenital hypothyroidism [Pax8(–/–)] display a significant rise in hepatic
triglyceride levels, accompanied by a reduction in hepatic apoB RNA editing.
The synthesis of apoB is regulated by both T3 and T4, which facilitate the
secretion of VLDL [31]. An in-depth
examination of these processes demonstrates that THs effectively enhance
both the lipolysis and liponeogenesis in order to regulate lipid balance.
Nevertheless, studies have indicated that the levels of TH within the liver
and/or the functioning of TH communication could be reduced in individuals
with NAFLD, leading to an imbalance in the regulation of liver fat [32].
In a study utilizing a rat model of NAFLD, it was found that the
administration of T3 improves liver steatosis caused by a choline-methionine
deficient (CMD) diet. Not only does this impact occur through the
stimulation of fatty acid oxidation, but it is also accomplished by
suppressing the activation of inflammatory pathways, including the JNK and
STAT3 pathways [33]. Studies have
demonstrated that THs can trigger lipophagy in human hepatic cells and mouse
liver through a TR-dependent mechanism. Autophagy plays a crucial part in
the transportation of lipids to the mitochondria for β-oxidation, suggesting
that it is instrumental in TH-induced fatty acid β-oxidation in hepatic
cells [34]. Furthermore, T3 plays a
crucial role in controlling the turnover and functioning of mitochondria in
hepatic cells. It achieves this by promoting the synthesis of new
mitochondria and facilitating mitophagy, with both processes relying on each
other [35]. Lately, there has been an
observation of THs increasing the activity of pathways that involve
PGC1α-nuclear respiratory factor 1-mitochondrial transcription factor A and
estrogen-related receptor alpha for mitochondrial biogenesis and degradation
of mitochondria (mitophagy) [36]
[37]. Taken together, in order to
eliminate faulty mitochondria, minimize cell damage caused by reactive
oxygen species (ROS) produced during fatty acids β-oxidation, and maintain
hepatic lipid homeostasis, it may be essential for T3-treated cells to
simultaneously undergo mitophagy, mitochondrial biogenesis, and enhanced
mitochondrial function. DIO1, a hepatic enzyme, transforms T4 into the
active T3, controlling the levels of triglycerides and cholesterol in the
liver. In a simulation of early NAFLD, the expression and functioning of the
hepatic DIO1 gene were enhanced and linked to a higher ratio of T3/T4. This
could potentially function as a compensatory mechanism to decrease the
buildup of fat in the liver and hinder the advancement of NASH [38]. Nevertheless, this defensive
benefit vanishes in individuals and rodents with progressed NAFLD, as
indicated by reduced levels and functionality of DIO1, hindering the
transformation of T4 into active T3 [39].
The capacity of THs is to decrease the levels of circulating proprotein
convertase subtilisin/kexin type 9 (PCSK9). LDLR degradation is promoted by
PCSK9 when it binds to the LDLR located on the surface of cells and
facilitates its breakdown in lysosomes. Decreased LDLR results in reduced
liver uptake of LDL-C, leading to elevated levels of LDL-C in the plasma
[3]. The connection between
hypothyroidism and elevated levels of PCSK9 in the bloodstream is
demonstrated [40]. In contrast, the
presence of hyperthyroidism and the administration of KB2115, a
liver-specific TH analog, result in decreased levels of PCSK9, lipoprotein
cholesterol, apoB, apoAI, and lipoprotein(a) in the bloodstream [41]. Additionally, THs also stimulate
cholesterol 7-α-hydroxylase (CYP7A1), leading to the conversion of
cholesterol into bile acids and exerting a hypocholesterolemic effect [42]. Moreover, THs promote the release
of cholesterol into bile by stimulating the gene expression of the mouse ATP
binding cassette subfamily G member (ABCG5/G8) complex, regardless of the
impact of LXRα [43].
Collectively, thyroid hormones regulate liver metabolism in a synchronized
fashion, although sometimes exhibiting conflicting effects. Despite the fact
that THs promote lipogenesis, hyperthyroidism leads to a decrease in overall
hepatic triglyceride levels due to the dominant catabolic effects of THs on
hepatic lipids surpassing fatty acid synthesis. The mobilization,
degradation and β-oxidation of fatty acids by THs help the decrease of liver
steatosis. The functions of THs in the pathophysiology of NAFLD are
summarized schematically in [Fig.
1].
Fig. 1 The functions of THs in the pathophysiology of NAFLD.
ChREBP: Carbohydrate-responsive element-binding protein; SREBP-1c:
Sterol regulatory element-binding protein-1c; LXR: Liver X receptor;
FAS: Fatty acid synthase; ACC: Acetyl-CoA carboxylase; Me: Malic
enzyme; Spot14: TH-responsive Spot 14 homologue; SCD1: Stearoyl-CoA
desaturase 1; DNL: De novo lipogenesis; FAT: Fatty acid translocase;
FABP: Fatty acid binding protein; FA: Fatty acid; TG: Triglyceride;
ATGL: Adipose triglyceride lipase; HL: Hepatic lipase; CPT1α:
Carnitine palmitoyltransferase-1α; PPARα: Peroxisome
proliferator-activated receptor-α; MCAD: Medium-chain acyl-CoA
dehydrogenase; PDK4: Pyruvate dehydrogenase kinase isoform 4; UCP2:
Uncoupling protein 2; ERRα: Estrogen-related receptor-α; PGC1α:
PPARγ co-activator 1α; NRF1: Nuclear respiratory factor 1; mtTFA:
Mitochondrial transcription factor A; CYP7A1: Cholesterol
7α-hydroxylase; PCSK9: Pro-protein convertase subtilisin/kexin type
9; VLDL: Very-low-density lipoproteins; LDL: Low-density
lipoprotein; Abcg5/Abcg8: ATP-binding cassette subfamily G member
5/8.
Effects of TSH on hepatic lipid metabolism
The specific TSHR mediates the biological function of TSH, being present not
only on the membrane of thyroid follicular cells but also in various
extra-thyroidal tissues and cells, such as hepatocytes [44]. The activation of hepatic SREBP-1c
through the cyclic AMP (cAMP)/protein kinase A (PKA)/PPARα pathway and the
reduction of AMP-activated protein kinase (AMPK) activity can be a direct
consequence of elevated TSH levels, leading to the development of
hepatosteatosis. As a result, the upregulation of genes linked to
lipogenesis is further amplified, ultimately resulting in increased
steatogenesis [44]. Moreover, it has
been noted that recombinant TSH can enhance the production of hepatic
3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an enzyme that
controls the rate of cholesterol synthesis, by activating the
cAMP/PKA/cyclic adenosine monophosphate-responsive element binding protein
(CREB) signaling pathway in human liver cells [45]. Different research discovered that
the administration of TSH suppressed the synthesis of hepatic bile acid
through a signaling pathway involving SREBP-2, HNF-4α, and CYP7A1 in rats
that had their thyroid removed and were given T4 supplements [46]. This indicates that TSH plays a
significant role as a pathophysiological regulator of liver bile acid
homeostasis, regardless of THs. Due to the fact that bile acids serve as the
main mechanism for eliminating surplus cholesterol from liver cells, a
reduction in bile acid concentration leads to elevated levels of cholesterol
in both the liver and bloodstream. In a recent study, it was found that the
levels of PCSK9 and increased LDL-C concentrations were positively
associated with serum TSH concentrations [47]. The vitro study discovered that recombinant human TSH
(rhTSH) increased the levels of PCSK9 mRNA and protein, while also reducing
the expression of LDLR and hindering the process of LDL-C endocytosis in
liver cells [47]. Significantly, the
use of rhTSH reduced T3 concentrations in thyroidectomized patients
receiving levothyroxine, resulting in adverse alterations in lipid profiles.
These changes included elevated levels of serum apoB, lipoprotein(a), and
triglycerides, as well as decreased levels of HDL-C [48]. These findings imply that TSH
could potentially impact lipid metabolism in the liver and contribute to the
progression of NAFLD.
Effects of thyroid disfunction on NAFLD
The presence of hypothyroidism has been linked to a decrease in the rate at
which triglycerides are removed from the bloodstream and an elevation in the
levels of intermediate LDL (IDL). Hence, hypothyroid patients may experience
the development of NAFLD due to elevated levels of LDL and the accumulation
of triglycerides in the liver [49]. In
addition to impacting lipid metabolism, hypothyroidism has been linked to
increased levels of oxidative stress indicators, including malondialdehyde.
This suggests that oxidative stress plays a crucial part in the development
of hypothyroidism-induced NAFLD [50].
Certainly, there exists a robust connection between insulin resistance and
the excessive accumulation of triglycerides in liver cells. By doing so,
this connection enhances the lipolysis in fat cells and the movement of free
fatty acids to the liver [51]. The
presence of insulin resistance is linked to hypothyroidism [3], potentially elucidating a
pathogenetic mechanism for the development of NAFLD caused by
hypothyroidism. Leptin, an adipokine, promotes hepatic insulin resistance
and hepatic fibrogenesis. Plasma leptin levels were significantly elevated
in hypothyroid rats or subjects. Furthermore, T3 and T4 levels are inversely
correlated with leptin. Treatment of hypothyroidism resulted in a reduction
in the elevated plasma leptin levels. The results suggest that leptin may
play a role in the connection between the thyroid and liver, as well as in
the development of NAFLD [52].
The comprehensive study of hyperthyroidism's effects on NAFLD has not
been conducted in comparison to hypothyroidism. Earlier research findings on
thyroid dysfunction and hepatic lipid peroxidation indicate that increased
levels of THs in a state of hyperthyroidism can boost the metabolic rate,
potentially resulting in excessive oxidation of liver lipids, oxidative
phosphorylation, and the generation of ROS, ultimately leading to liver cell
damage [53]. In fact, during a state
of hyperthyroidism, an overabundance of THs triggers apoptosis in liver
cells through the activation of pathways involving death receptors [54]. Furthermore, the excessive
presence of THs may also play a part in the development of NAFLD by
promoting increased gluconeogenesis and glycogenolysis, which are known to
have diabetogenic effects on the liver.
Researchers discovered that in individuals with biopsy-confirmed NASH who
underwent bariatric surgery, there was a negative correlation between the
mRNA expression of TRβ and the activity of steatosis. This suggests that,
besides the systemic concentrations of THs, there could be tissue
insensitivity to circulating THs which plays a role in the development of
NASH [55].
To summarize, the development of NAFLD may be influenced by hyperthyroidism,
hypothyroidism, and resistance to THs. Finding the right balance is crucial
for maintaining homeostasis.
Therapeutic potential of THs, TH mimetics, and TH metabolites in
NAFLD
Considering the beneficial impacts of THs on liver metabolism and maintaining
energy balance, particularly in reducing LDL-C and triglyceride levels, it
is logical to deduce that THs could have therapeutic value in the treatment
of NAFLD. Experimental animal models of NAFLD have demonstrated that the
exogenous administration of T3 can decrease hepatic fat accumulation and
improve steatohepatitis [33],
supporting this viewpoint. Additionally, by administering suitable
levothyroxine supplementation, the occurrence of NAFLD in individuals with
notable subclinical hypothyroidism (TSH≥10 mIU/l) dropped from 48.5% to
24.2% [56]. Nevertheless, the
physiological effects of THs impact nearly all bodily organs. Consequently,
the introduction of external THs unavoidably induces unfavorable effects
beyond the liver, particularly in the cardiovascular system and
musculoskeletal system. These effects hinder the timely implementation of
THs in treating hyperlipidemia and NAFLD [57]. The actions of THs are mediated by two isoforms of nuclear
hormone receptors, namely TRα and TRβ. TR isoforms are expressed in a
tissue-specific manner, with TRα being the primary form found in bone and
heart. Cardiovascular diseases, especially tachycardia and heart failure,
have been linked to the activation of TRα. In contrast, the liver primarily
expresses TRβ and plays a crucial role in regulating metabolic balance via
various complex signaling pathways [21]. Furthermore, it was noted by Araki et al. [58]
[59] that in TRβPV mice (referred to as TRβ gene mutation), there
was an augmentation in liver lipid buildup caused by heightened lipogenic
gene expression and reduced fatty acid β-oxidation, while no notable
alteration occurred in white adipose tissue. On the other hand, the liver
fat content and white adipose tissue mass were decreased in TRαPV mice due
to the suppression of lipogenic gene expression caused by the TRα gene
mutation. The results indicate that the two TR isoforms have a preference
for regulating distinct pathways related to lipid metabolism.
Hence, optimal substances that aim at TRβ can efficiently diminish hepatic
steatosis, inflammation, and fibrosis while preserving liver specificity
without affecting the HPT axis. Furthermore, their strong specificity for
TRβ inhibits unwanted systemic effects in the bone/cartilage and heart
caused by the TRα isoform.
In animal models of NAFLD, sobetirome (GC-1) and eprotirome (KB2115), the
initial pair of synthetic TRβ agonists, have shown the capacity to decrease
intrahepatic lipid content and lipoperoxidation [33]
[60]. Moreover, administration of GC-1 effectively suppressed the
hepatocarcinoma proliferation while having no impact on β-catenin and its
downstream targets [61]. Despite the
positive outcomes, GC-1 was terminated after the phase I clinical trial due
to insufficient funding and several experimental findings of hyperglycemia
and hyperinsulinemia, suggesting a decline in insulin responsiveness [60]. According to reference [57], KB2115 was stopped due to the
occurrence of cartilage damage and hepatic toxicity in dogs after prolonged
treatment.
Recently, a new molecule has surfaced that shows promise as a combination of
glucagon and T3, aiming to merge the lipid-reducing properties of glucagon
with the beneficial energy-burning effects of T3. Administering this
glucagon/T3 combination to obese mice led to lower levels of lipids in the
blood, reduced fat tissue, the reversal of NASH, decreased buildup of
atherosclerotic plaque, and improved glucose metabolism. While avoiding
thyrotoxicosis and the hyperglucotoxicity linked to glucagon [62], it managed to produce these
outcomes. The hybrid molecule has the potential to combine the metabolic
advantages of each component while avoiding the usual side effects of these
hormones, demonstrating its synergistic potential. Although additional
research is required to progress this compound to clinical trials, it is
important to mention that the combination of glucagon and T3 shows potential
as a selective thyromimetic for treating NAFLD.
MB07811, alternatively referred to as VK2809, is a prodrug that can be
activated by hepatic cytochrome P450 (CYP) isoenzyme CYP3A into an active
substance when taken orally. Through structural improvements, MB07811 has
been designed to avoid adverse effects on extrahepatic tissues, such as the
heart. MB07811 has been demonstrated in preclinical studies to reduce
hepatic triglyceride levels and decrease plasma triglyceride and cholesterol
levels without causing liver fibrosis, histological liver damage, or
negative impacts on body weight and blood glucose levels [63]
[64]. Furthermore, Cable et al. have proposed that the
administration of MB07811, a recognized hepatic thyroid receptor agonist,
results in the augmentation of hepatic mitochondrial respiration rates and
the elevation in plasma acylcarnitine levels. Consequently, this leads to an
enhancement of hepatic fatty acid oxidation and a decrease in hepatic
steatosis [64]. MB07811 treatment
decreased hepatic triglyceride levels and hepatosteatosis in cases of
Glycogen Storage Disease Ia (GSD Ia), which can cause steatohepatitis,
cirrhosis, and an elevated likelihood of hepatocellular adenomas and cancer
due to elevated levels of glycogen and triglycerides in the liver. By
stimulating impaired hepatic autophagy flux, boosting the biogenesis of
mitochondria, and facilitating the oxidation of fatty acids, it accomplished
this feat [65]. A phase IIa clinical
trial has been completed to assess the efficacy, safety, and tolerability of
VK2809 in lowering LDL-C and liver fat content when administered in patients
with primary hypercholesterolemia and NAFLD (NCT02927184). The liver fat
content decreased significantly from baseline after 12 weeks of treatment,
with reductions of 53.8% for the daily 5 mg dose, 56.5% for every other day
10 mg dose, and 59.7% for the daily 10 mg dose, in comparison to a 9.4%
reduction in the placebo group. At the conclusion of the study, a hepatic
fat reduction of≥30% was attained by 88% of the patients who received VK2809
treatment [66]. Importantly, VK2809
was well tolerated, without reports of adverse effects on the heart or bone
among patients. Patients with biopsy-confirmed NASH (NCT04173065) are
enrolled in a registered phase IIb clinical trial. This novel prodrug holds
the promise of bringing about beneficial clinical effects for treating
lipid-related liver pathologies, including NAFLD.
Resmetirom, alternatively called MGL-3196, is an orally administered
HepDirect TRβ agonist that has been developed more recently. Resmetirom
demonstrated improvement in the NAFLD activity score and reduction in
hepatic fibrosis in a mouse model of NASH with fibrosis. To accomplish this,
it decreased the levels of α-smooth muscle actin and suppressed the
expression of fibrogenesis-related genes, including collagen 1α1, lysyl
oxidase-like 2, and hydroxysteroid 17β-dehydrogenase 13 [67]. During the phase II of the
clinical trial, which included 125 adults diagnosed with NASH through
biopsy, individuals who received resmetirom at either 80 or 100 mg per day
witnessed a significant decrease of 32.9% in hepatic fat, as determined by
MRI-proton density fat fraction (MRI-PDFF), in contrast to a 10.4% reduction
observed in patients who were given a placebo over a period of 12 weeks
(NCT02912260). Following 36 weeks of therapy, resmetirom exhibited a 37.3%
decrease in liver fat in contrast to an 8.5% decrease in the group treated
with a placebo. At week 36, resmetirom treatment effectively decreased
atherogenic lipids like LDL-C and triglycerides, along with markers of
fibrosis such as liver stiffness and N-terminal type III collagen
pro-peptide. Resmetirom had no impact on the HPT axis, showed no adverse
effects on the heart or bone related to TRα, and reduced elevated liver
enzyme levels in the bloodstream. Currently, there are ongoing clinical
trials (NCT03900429, NCT04951219, and NCT04197479) examining the
effectiveness of MGL-3196 therapy for individuals diagnosed with NAFLD and
NASH. The MAESTRO Phase III NASH clinical studies yielded promising
outcomes, including the following key findings: (1) Administering MGL-3196
for 3 months resulted in a notable decrease in liver fat, which strongly
predicted subsequent resolution of NASH and reduction in fibrosis as
confirmed by liver biopsy; (2) Daily oral doses of 80 mg and 100 mg of
MGL-3196 led to a minimum 50% and over 60% reduction in liver fat,
respectively, accompanied by a decrease in fibrosis by over 60%; and (3)
MGL-3196 demonstrated significant reduction in markers indicating net
collagen deposition in the liver, suggesting its potential as an
anti-fibrotic agent.
3,5,-l-Diiodothyronine (T2), a catabolite of T3, is derived from the
deiodination of T3 via DIO2. In several experimental models of
HFD, the administration of T2 has demonstrated the ability to decrease the
buildup of fat in the liver, enhance hepatic fatty acid β-oxidation, and
alleviate oxidative stress within mitochondria, ultimately leading to the
reversal of hepatic steatosis. Furthermore, T2 administration has been found
to prevent HFD-induced insulin resistance [68]
[69]. A deeper
mechanistic investigation revealed that T2 does not act through TRβ but
directly activates hepatic nuclear sirtuin 1 (SIRT1). The activation of
SIRT1 controls downstream genes related to lipid processing and
mitochondrial function, ultimately enhancing insulin sensitivity [69]. Interestingly enough, T3 regulates
hepatic genes, lipid metabolism, and mitochondrial activity through direct
interaction of SIRT1 with TRβ. In addition to activating oxidative pathways,
T2 can increase the mRNA expression of apoB, which is the primary protein
constituent of VLDL, thereby enhancing lipid secretion instead of
accumulation. Specifically, T2 might inhibit the pathways that result in the
accumulation of fats in lipid droplets through the regulation of PPAR-α, -γ,
and -δ genes [70]. The results
indicate that T2 has thyromimetic properties and shows certain advantageous
impacts on liver metabolism, similar to T3. This implies that T2 is not
merely a passive metabolite, as initially proposed, and could have potential
as a medication for addressing liver conditions associated with lipids, such
as NAFLD.
In animal experiments, the latest TRβ-specific activators, IS25 and its
prodrug TG68, have demonstrated enhanced hepatocyte proliferation and
mitotic activity, while avoiding T3-related adverse effects like cardiac or
renal hypertrophy and proliferation of pancreatic acinar cells [71]. Moreover, the hepatocyte
proliferation caused by IS25 and TG68 did not lead to liver damage, as
evidenced by the levels of transaminases in the blood and the count of
hepatocytes positive for Caspase-3. These factors showed no notable
disparity between the control group and the rats treated with TG68 or IS25
[71]. Hence, additional clinical
investigations are required to validate the effectiveness and security of
these substances on the proliferation of liver cells.
Taken together, TH metabolites and TRβ-selective agonists present a promising
advantage in the management of NAFLD. Nevertheless, the long-term safety and
effectiveness of these substances require additional assessment in
meticulously conducted clinical trials.
