Nonalcoholic fatty liver disease (NAFLD) is defined as the accumulation of fat in the liver in the absence of alcohol consumption and other causes of chronic liver disease, such as viral hepatitis or drugs.1 NAFLD is now recognized as one of the most common liver diseases worldwide, affecting a substantial proportion (10%-25%) of the general population of several countries.2, 3 Clinicopathologically, NAFLD encompasses a wide spectrum of histological abnormalities, including various degrees of steatosis, lobular inflammation, and fibrosis of the liver.4 The histological picture seems to be related to clinical outcomes.5 Thus, while pure hepatic steatosis has a benign clinical course,6 the presence of necroinflammatory changes and pericellular fibrosis (where the term nonalcoholic steatohepatitis [NASH]7 is applied) is associated with an increased risk of developing advanced fibrosis, cirrhosis, and hepatocellular carcinoma.2, 8, 9 Data from different sources allows for estimating that up to one-third of subjects with NAFLD have NASH.10
Therapeutic interventions in NAFLD are mainly based on lifestyle changes, including diet and exercise.11, 12 Currently, there are no approved pharmacological therapies for NAFLD, but because insulin resistance is almost universally present in patients with this condition, drugs that increase insulin sensitivity are currently undergoing extensive evaluation and hold promise as therapeutically effective agents.7, 13 Several other agents, such as antioxidants, hepatoprotective compounds, and drugs to induce weight reduction, have been evaluated and have shown inconclusive or no effects.12
In this issue of HEPATOLOGY, Cable and co-workers14 conducted an interesting animal study assessing the effects of liver-selective thyroid hormone receptor (TR) agonists on liver steatosis in rodents. Before getting into details of their work, a word about the so-called thyromimetic compounds15, 16 is in order.
It is well known that TR activation has beneficial effects including lowering of low-density lipoprotein cholesterol and a reduction in whole-body adiposity and weight. For this reason, thyroid hormone agonists were among the first antiobesity agents. However, an excess of thyroid hormone is associated with unwanted effects, particularly on the heart (including tachycardia and sudden death) but also on bone and skeletal muscle. Thus, drugs devoid of these untoward effects but harnessing the beneficial effects of thyroid hormone (generically termed as thyromimetics) would be useful for the treatment of both obesity and hypercholesterolemia.16 The existence of distinct isoforms of TRs and knowledge of their tissue distribution, regulation, and crystal structure has shown that this therapeutic aim is in fact possible.16 There are two TR isoforms (α and β) that are encoded by two genes. TRα and TRβ isoforms predominate in the heart and liver, respectively, and splice variants of each gene have been described. Four of them (TRα1, TRα2, TRβ1, and TRβ2) are known to be expressed at the protein level in vivo.17 The synthesis of compounds that selectively bind TRβ1 has been carried out in recent years.16 They have been tested on animals, showing that they are able to increase total body oxygen consumption and to lower weight and serum cholesterol and triglyceride levels in rodents.15, 16
Recently, a human study18 showed that in a small group of moderately overweight and hypercholesterolemic subjects, short-term treatment with the oral thyromimetic Eprotirome (KB2115) induced a potent and rapid low-density lipoprotein reduction. The drug was found to be safe and well tolerated and in the dose that it was given did not provoke changes in metabolic rate or weight loss or detectable effects on the heart, suggesting that the pharmacological selectivity was achieved. More recently, agents with specific liver selectivity have been developed based on the so-called HepDirect liver-targeting approach.19 This class of drugs was developed taking advantage of the poor distribution of phosphonic acid–based drugs to extrahepatic tissues. A phosphonate-containing TR agonist is predominantly taken by the liver with a high first-pass extraction and further metabolism by cytochrome P450 3A. This is essential in limiting the extrahepatic side effects associated with this class of agents. MB07811 is the main compound of this type. It is converted into the active drug MB07344 in liver microsomes, which allows for a high degree of liver targeting of MB07344.
By using several experimental approaches, Cable et al. showed that MB07811 has antisteatotic activity that is able to reduce hepatic triglyceride levels in both normal and metabolically-challenged animal models, including ob/ob mice, Zucker rats, and mice with diet-induced obesity. The main mechanism underlying MB07811 effects seems to be an increased metabolic rate in liver and specifically an increased rate of mitochondrial β-oxidation. Evidence indicating this includes an increase in the messenger RNA (mRNA) levels of carnitine palmitoyltransferase-I (CPT-1), a rate-limiting enzyme in the fatty acid oxidation cycle,20 elevated levels of short and intermediate length acyl-carnitine species in plasma, increased mitochondrial respiration rates observed in ex vivo liver preparations, and increased activity of hepatic mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH), an enzyme which is important to energy production and dissipation. Decreased mRNA levels of Apo-C3, an inhibitor of hepatic lipase activity, might also contribute to activation of fatty acid oxidation pathways. Selectivity of MB07811 was convincingly demonstrated by showing that although in the liver T3 and MB07811 had similar effects on the TR-responsive genes evaluated (i.e., reduction in mRNA levels of sterol regulatory element binding protein-1c [SREBP-1c] and apolipoprotein C3 [ApoC3] and an increase in A1 [ApoA1] and peroxisome proliferator-activated receptor coactivator-1 [PGC-1] transcripts), this agent did not increase fasting plasma free fatty acid (FFA) levels or reduce the weight of the epidydimal fat pad, both of which are known effects of extrahepatic TR activation. Moreover, MB07811 neither affected heart weight nor decreased pituitary thyroid-stimulating hormone mRNA, showing that in therapeutic doses it is devoid of measurable extrahepatic effects. In addition, treatment with MB0711 has lowering effects on both serum cholesterol and triglyceride. Collectively, the work of Cable et al. convincingly demonstrates that selective activation of hepatic TR prevents or reverses fatty liver and points to a new approach to treat NAFLD based on selectively burning hepatic fat. Interestingly, a very recent report by Perra et al.21 independently reproduces the findings of Cable and colleagues using GC-1, another TRβ1 selective activator.
When considering the potential use of agents with an antisteatotic activity in NAFLD, one has to ask if this approach would be sufficient and safe for treating patients with NAFLD. From a strictly hepatological point of view, those patients with simple steatosis do not need specific therapy because their clinical course is benign. Lifestyle changes, including diet and exercise, are warranted because of general medical considerations and possibly due to the significant association of NAFLD with increased cardiovascular risk.22 For the hepatologist, those patients with the aggressive forms of the disease (i.e., patients with NASH) are the ones in need of effective therapy aiming to halt progression of the liver disease and eventually reverse fibrosis.23 It is possible that burning hepatic fat with thyromimetics may not be effective enough to achieve these goals in NASH.
A key issue in the NAFLD field is why some individuals develop the aggressive form of the disease and others do not.24 Indeed, the proportion of subjects who will show evidence of disease progression or develop complications of end-stage liver disease is rather small.2 The predominant view of the disease pathophysiology points to the occurrence of a sequential evolution from bland steatosis to NASH due to either a second hit or to worsening of insulin resistance.24, 25 This view might be wrong and the possibility exists that patients with bland steatosis belong to a completely different population than those with NASH from the very beginning of the disease. Recent data suggesting that hepatic steatosis may indeed protect against the development of advanced disease is in line with this view. Work from Yamaguchi et al.26 indicates that inhibition of triglyceride accumulation in the liver of mice with steatohepatitis results in increased lobular inflammation and fibrosis. These data suggest that variations in the hepatic capacity to store fatty acids in the form of triglycerides may significantly influence the progression of liver damage in NAFLD. Thus, while the majority of NAFLD patients manage the peripheral FFA flow from visceral adipose tissue into the liver, storing them as triglycerides (“good fat storers”), a minority (“bad fat storers”) could not do so and develop NASH as a result of direct hepatic lipotoxicity (Fig. 1) and systemic alterations associated with obesity and insulin resistance, including cytokine/adipokine imbalance. Good fat storers may develop progressive disease if a concurrent injury (i.e., viral hepatitis, alcohol, drugs, etc.) is present according to the “second hit” theory.25 These data also help to explain why steatosis often decreases or disappears in the advanced stages of the disease (“burned NASH”).1 The recent finding by Romeo et al.27 that variations of the PNPLA3 (Patatin-like phospholipase domain containing 3) gene, which encodes a triacylglycerol lipase that mediates triacylglycerol hydrolysis in both adipose tissue and the liver, contribute to the observed interindividual differences in hepatic fat content is in line with the concept of good and bad hepatic fat storers. However, the function of the reported variants in PNPLA3 associated with increased liver fat is still unknown and the precise role of PNPLA3 in liver fat metabolism remains to be determined.27
From the ideas mentioned above, some potential limitations of a liver-specific antisteatotic agent, such as MB07811, can be derived. First, considering the systemic nature of the disease, burning hepatic fat may not be sufficient for patients with NASH (those who really need therapy) because the metabolic imbalance, particularly peripheral insulin resistance, would continue and the beneficial effect of thyromimetics could be counteracted by increased lipogenesis in the liver or lipolysis in adipocytes. Second, systemic fibrogenic stimuli, such as hyperinsulinemia, which can stimulate fibrogenesis by way of up-regulation of connective tissue growth factor and direct interactions with hepatic stellate cells,28 or hypoadiponectinemia, would also persist and it is likely that other fibrogenic pathways remain unaffected by thyromimetic agents. Finally, burning hepatic fat may not be appropriate in a liver that already has some degree of damage. An increased metabolic rate might be harmful to healthy but vulnerable hepatocytes that remain in the liver, and worsening of inflammation and fibrosis may occur as observed in some obese patients with NASH undergoing bariatric surgery and rapid weight loss.29 In this regard, it has to be taken into account that the experimental models used by Cable et al. do not exhibit significant inflammation or fibrosis and therefore the effect of MB07811 in this setting remains unknown.
In summary, the work of Cable et al. along with the recent report of Perra et al.21 indicate that very soon we will have available a new family of agents with antisteatotic activity due to their thyromimetic nature. The therapeutic potential of these agents in the treatment of NAFLD and particularly in NASH will need to be demonstrated in well-conducted clinical trials.