Cross-Talk Between Thyroid Disorders and Nonalcoholic Fatty Liver Disease: From Pathophysiology to Therapeutics

Abstract

The medical community acknowledges the presence of thyroid disorders and nonalcoholic fatty liver disease (NAFLD). Nevertheless, the interconnection between these two circumstances is complex. Thyroid hormones (THs), including triiodothyronine (T3) and thyroxine (T4), and thyroid-stimulating hormone (TSH), are essential for maintaining metabolic balance and controlling the metabolism of lipids and carbohydrates. The therapeutic potential of THs, especially those that target the TRβ receptor isoform, is generating increasing interest. The review explores the pathophysiology of these disorders, specifically examining the impact of THs on the metabolism of lipids in the liver. The purpose of this review is to offer a thorough analysis of the correlation between thyroid disorders and NAFLD, as well as suggest potential therapeutic approaches for the future.

Keywords

thyroid disorders - NAFLD - pathophysiology - therapeutics

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.

Conclusions and Perspectives

Currently, there are no medications approved by the FDA for the treatment of NAFLD. Hence, elucidating the pathophysiology and fundamental molecular mechanisms aids in the creation of targeted medications for NAFLD, aiming to impede or potentially reverse its advancement via diverse pathways.

NAFLD pathogenesis is multifaceted and incompletely understood. In recent research, the involvement of alterations in cellular TH signaling in NAFLD have been shown. Moreover, preliminary and population-based research suggest that thyroid malfunction is linked to an elevated likelihood of developing NAFLD, regardless of other factor that may contribute to the risk. Furthermore, the use of various TRβ-specific T3 derivatives, like resmetirom (MGL-3196) and the prodrug VK2809 (MB07811) with HepDirect action, has demonstrated the potential effectiveness of T3 as a medicinal treatment for halting the advancement of NAFLD.

Metabolism is a complicated, systemic issue that involves multiple organs. The discovery of a compound that specifically targets the liver and TRβ may still face challenges due to the potential interference of external factors, which can complicate its functions in unexpected ways. This can make it even more challenging to design research and may also impose limitations on the reliability and credibility of findings obtained through the current research model. Henceforth, upcoming investigations may employ novel methodologies, like the analysis of extensive datasets, to concentrate on the advantageous impacts of thyromimetics treatment on hepatic steatosis, fibrosis, and lipid levels, while assessing their detrimental effects on cardiovascular health and bone density.

Author Contributions

Luxia Jiang, Yan Yang, and Jiyuan Xiao contributed to the concept and design of the study; acquisition of the data; analysis and interpretation of the data; Yan Yang and Wen Qiu drafted the manuscript. Luxia Jiang critically revised the manuscript.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgement

This research was funded by the National Natural Science Foundation of China (81960165), the Health Industry Scientific Research Project of Gansu Province (GSWSKY2018–35), and the “Cuiying Science and Technology Innovation” program of Lanzhou University Second Hospital (CY2018-MS01).

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Publication History

Received: 16 December 2023

Accepted after revision: 26 February 2024

Accepted Manuscript online:
26 February 2024

Article published online:
05 April 2024