Thyroid hormones (THs) play critical roles in the differentiation, growth, metabolism, and physiological function of virtually all tissues. TH binds to receptors that are ligand-regulatable transcription factors belonging to the nuclear hormone receptor superfamily. Tremendous progress has been made recently in our understanding of the molecular mechanisms that underlie TH action. In this review, we present the major advances in our knowledge of the molecular mechanisms of TH action and their implications for TH action in specific tissues, resistance to thyroid hormone syndrome, and genetically engineered mouse models.

It has been known for a long time that thyroid hormones have prominent effects on hepatic fatty acid and cholesterol synthesis and metabolism. Indeed, hypothyroidism has been associated with increased serum levels of triglycerides and cholesterol as well as non-alcoholic fatty liver disease (NAFLD). Advances in areas such as cell imaging, autophagy and metabolomics have generated a more detailed and comprehensive picture of thyroid-hormone-mediated regulation of hepatic lipid metabolism at the molecular level. In this Review, we describe and summarize the key features of direct thyroid hormone regulation of lipogenesis, fatty acid β-oxidation, cholesterol synthesis and the reverse cholesterol transport pathway in normal and altered thyroid hormone states. Thyroid hormone mediates these effects at the transcriptional and post-translational levels and via autophagy. Given these potentially beneficial effects on lipid metabolism, it is possible that thyroid hormone analogues and/or mimetics might be useful for the treatment of metabolic diseases involving the liver, such as hypercholesterolaemia and NAFLD.

Summary The glucocorticoid receptor (GR), like other eukaryotic transcription factors, regulates gene expression by interacting with chromatinized DNA response elements. Photobleaching experiments in living cells indicate that receptors transiently interact with DNA on the time scale of seconds and predict that the response elements may be sparsely occupied on average. Here, we show that the binding of one receptor at the glucocorticoid response element (GRE) does not reduce the steady-state binding of another receptor variant to the same GRE. Mathematical simulations reproduce this non-competitive state using short GR/GRE residency times and relatively long times between DNA binding events. At many genomic sites where GR-binding causes increased chromatin accessibility, concurrent steady-state binding levels for the variant receptor are actually increased, a phenomenon termed assisted loading. Temporally sparse transcription factor-DNA interactions induce local chromatin reorganization, resulting in transient access for binding of secondary regulatory factors.

Caffeine is one of the world's most consumed drugs. Recently, several studies showed that its consumption is associated with lower risk for nonalcoholic fatty liver disease (NAFLD), an obesity-related condition that recently has become the major cause of liver disease worldwide. Although caffeine is known to stimulate hepatic fat oxidation, its mechanism of action on lipid metabolism is still not clear. Here, we show that caffeine surprisingly is a potent stimulator of hepatic autophagic flux. Using genetic, pharmacological, and metabolomic approaches, we demonstrate that caffeine reduces intrahepatic lipid content and stimulates b-oxidation in hepatic cells and liver by an autophagy-lysosomal pathway. Furthermore, caffeine-induced autophagy involved down-regulation of mammalian target of rapamycin signaling and alteration in hepatic amino acids and sphingolipid levels. In mice fed a high-fat diet, caffeine markedly reduces hepatosteatosis and concomitantly increases autophagy and lipid uptake in lysosomes. Conclusion: These results provide novel insight into caffeine's lipolytic actions through autophagy in mammalian liver and its potential beneficial effects in NAFLD. (HEPATOLOGY 2014;59:1366-1380 See Editorial on Page 1235 C affeine is one of the most widely consumed drugs in the world. Although its effect on whole-body metabolism and fat oxidation has been well documented in both animals and humans, [1][2][3] little is known about its direct action on the liver.The liver is the major site for fatty acid oxidation (FAO) in mammals. Decreased turnover of hepatic lipid droplets can lead to the development of fatty liver disease in humans. 4 Recently, the rapid rise in the prevalence of obesity and diabetes in the general population has contributed to a parallel increase in nonalcoholic fatty liver disease (NAFLD) in many parts of the world. Currently, it is estimated that up to 46% of the adult U.S. population may have hepatosteatosis. 5 Presently, there are no effective drug therapies for NAFLD, currently considered a risk factor for type II diabetes. 6 Recently, several studies have shown that caffeine intake in humans and animals is inversely correlated with severity of NAFLD and type II diabetes, 7-11 but the mechanism for this action is not known.

For more than a century, thyroid hormones (THs) have been known to exert powerful catabolic effects, leading to weight loss. Although much has been learned about the molecular mechanisms used by TH receptors (TRs) to regulate gene expression, little is known about the mechanisms by which THs increase oxidative metabolism. Here, we report that TH stimulation of fatty acid β-oxidation is coupled with induction of hepatic autophagy to deliver fatty acids to mitochondria in cell culture and in vivo. Furthermore, blockade of autophagy by autophagy-related 5 (ATG5) siRNA markedly decreased TH-mediated fatty acid β-oxidation in cell culture and in vivo. Consistent with this model, autophagy was altered in livers of mice expressing a mutant TR that causes resistance to the actions of TH as well as in mice with mutant nuclear receptor corepressor (NCoR). These results demonstrate that THs can regulate lipid homeostasis via autophagy and help to explain how THs increase oxidative metabolism. IntroductionThyroid hormones (THs) have been known to stimulate basal metabolic rate for over a century (1, 2). Subsequent studies showed that THs induced energy expenditure in response to increased caloric intake (3). Later, several intracellular processes were shown to be involved in the calorigenic effects of THs. These included increased ATP expenditure due to increased Na + /K + -ATPase activity to maintain ion gradients in various tissues (4, 5) as well as reduced efficiency of ATP synthesis, particularly through the induction of uncoupling proteins (UCPs), which cause proton leakage in the electron transport chain of the mitochondria of target tissues (6, 7). However, despite these advances in our understanding of THs on cellular metabolism, none of these proposed mechanisms appears to be dominant. Currently, little is known about other mechanisms that might be utilized by THs to regulate energy consumption within the cell. This is particularly true for the events involved in the delivery of fatty acids to mitochondria, a necessary step in converting stored intracellular triglyceride fuel into ATP.The active form of TH, 3,3′5-triiodo-l-thyronine (T 3 ), is a critical regulator of cellular and tissue metabolism throughout the body. It controls gene expression in target tissues by binding to its cognate nuclear receptors (TRα and TRβ), which are ligand-inducible transcription factors. In the presence of T 3 , TH receptors (TRs) bind to TH response elements in the promoters of target genes and form coactivator complexes containing histone acetyltransferase activity to activate transcription (8). In the absence of T 3 , TRs recruit corepressors such as NCoR and silencing mediator of retinoid and thyroid receptors (SMRT), which together with transducin β-like protein 1 (TBL1) and histone deacetylase 3 (HDAC3)

LSD1 is a flavin dependent histone demethylase that oxidatively removes methyl groups from Lys-4 of histone H3. LSD1 belongs to the amine oxidase enzyme superfamily which utilize molecular oxygen to transform amines to imines that are hydrolytically cleaved to formaldehyde. In prior studies, it has been shown that monoamine oxidase inhibitory scaffolds such as propargylamines and cyclopropylamines can serve as mechanism-based inactivators of LSD1. Propargylamine-histone H3 peptide analogs are potent LSD1 inhibitors whereas small molecule antidepressant MAO acetylenic inhibitors like pargyline do not inhibit LSD1. In contrast, the small molecule MAO cyclopropylamine inhibitor tranylcypromine is a time-dependent LSD1 inhibitor but exo-cyclopropylamine-peptide substrate analog is not. To provide further insight into small molecule versus peptide relationships in LSD1 inhibition, herein we further our analysis of warheads in peptide scaffolds to include the chlorovinyl, endo-cyclopropylamine, and hydrazine-functionalities as LSD1 inactivators. We find that chlorovinyl-H3 is a mechanism-based LSD1 inactivator whereas endo-cyclopropylamine-H3 does not show time-dependent inactivation. The hydrazine-H3 was shown to be the most potent LSD1 suicide inhibitor yet reported, more than 20-fold more efficient in inhibiting demethylation than propargylamine-H3 derivatives. We re-explored MAO antidepressant agent phenelzine (phenethylhydrazine), previously reported to be a weak LSD1 inhibitor, and found that it is far more potent than previously appreciated. We show that phenelzine can block histone H3K4Me demethylation in cells, validating it as a pharmacologic tool and potential lead structure for anticancer therapy.Post-translational modification (PTM) of histones on lysines regulates gene expression by remodeling chromatin and is a central focus of epigenetic studies. 1, 2 Among the many PTMs that reversibly modify chromatin, lysine methylation provides for a rich array of biological readouts.3 , 4 For example, methylation of Lys-4 of histone H3 is a mark of gene activation, whereas Lys-9 methylation is more often associated with gene silencing. The relatively recent discovery of histone lysine demethylases has helped round out our understanding of the factors that control methyl-Lys stability. 5,6 Included among the histone demethylases are the flavin dependent enzymes LSD1 and LSD2 and the iron-dependent Jmj catalysts. [5][6][7] LSD1 is a member of the amine oxidase superfamily and utilizes a non-covalently bound FAD cofactor in the oxidative removal of methyl groups, specifically from Lys-4 of histone H3. 5,8 The catalytic cycle of methyl removal produces a molecule each of formaldehyde and *To whom correspondence should be addressed. pcole@jhmi.edu. Telephone: (410) 955-3023. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript H 2 O 2 while consuming O 2 (Scheme 1). 5,8 Dictated by the inherent limitations of the flavin chemistry, LSD1 can only function in the remo...

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