Editorial
Pituitary TSH controls bile salt synthesis Peter L.M. Jansen1,2,⇑, Frank G. Schaap1 1 Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO BOX 616, 6200 MD Maastricht, The Netherlands; 2Department of Gastroenterology and Hepatology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO BOX 616, 6200 MD Maastricht, The Netherlands
See Article, pages 1171–1179
Binding of thyroid-stimulating hormone (TSH, thyrotropin) to its receptor (TSHR) on the surface of thyroid follicular cells stimulates the formation and release of the active thyroid hormone (TH) triiodothyronine (T3), and its precursor, the prohormone thyroxine (T4) [1,2]. THs affect numerous biological processes through genomic as well as nongenomic actions involving nuclear TH receptors of the NR1A subfamily and specific members of the integrin family of plasma membrane receptors, respectively [1]. The liver is an important but somewhat undervalued target organ for TH action. Although most abundantly expressed in the thyroid gland, TSHR protein expression is detected amongst others in (pre)adipocytes, bone and kidney and this has led several groups to explore extrathyroidal actions of TSH [2]. In this issue, the group of Jiajun Zhao, which first reported on functional TSHR signaling in the liver [3–5], describes a direct effect of TSH on bile salt synthesis [6]. Bile salts act as emulsifiers of lipids, and as such are crucial for solubilization of biliary cholesterol and effective processing of diet-derived lipids. Levels of these biological detergents must be tightly controlled to prevent detrimental effects outside the gastrointestinal tract. In the liver, cholesterol is converted into bile salt conjugates by sequential action of at least 16 enzymes, and this pathway provides the major route for disposal of excess cholesterol [7]. Bile salt synthesis proceeds via either two routes, the classical pathway initiated by cholesterol-7a-hydroxylase (encoded by the CYP7A1 gene), and the acidic pathway initiated by enzymes that hydroxylate the side chain of cholesterol [7]. The classical pathway accounts for the bulk of newly synthesized
Keywords: Bile salts; Thyroid-stimulating hormone; CYP7A1; HNF4alpha. q DOI of original article: http://dx.doi.org/10.1016/j.jhep.2014.12.006. ⇑ Corresponding author. Address: Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO BOX 616, 6200 MD Maastricht, The Netherlands. E-mail address: [email protected] (P.L.M. Jansen). Abbreviations: TSH, thyroid-stimulating hormone; TSHR, TSH receptor; TH, thyroid hormone; NR, nuclear receptor; TRb, TH receptor b; HNF4a, hepatocyte nuclear factor 4a; FXR, farnesoid x receptor; FGF15/19, fibroblast growth factor 15/19; PI3K, phosphatidylinositol 3-kinase; SREBP, sterol regulatory elementbinding protein; TRH, TSH-releasing hormone; SHP, small heterodimer partner.
bile salts in rodents and human, with regulation exerted primarily at the level of CYP7A1 transcription [7,8]. The proximal CYP7A1 promoter contains overlapping binding sites for a number of positively and negatively acting transcription factors that together determine the overall transcriptional output. Members of the aforementioned family of nuclear receptors (NRs) that bind in this region include NR1A2/TRb, which mediates transcriptional regulation of CYP7A1 by THs, and NR2A1/HNF4a, a liver-enriched transcription factor that determines basal expression of CYP7A1 and a large number of other liverspecific genes [9]. It is this latter factor that is targeted by the newly uncovered hepatic action of TSH (Fig. 1). Using complementary approaches, Song et al. provide evidence that TSH is able to repress rodent Cyp7a1 expression in a manner independent of changes in total TH levels [6]. Firstly, in thyroidectomized rats with stable systemic levels of exogenously supplied T4, administration of recombinant TSH results in dosedependent lowering of Cyp7a1 activity and reduction of systemic and hepatic bile salt levels. Secondly, in Tshr/ mice in which hypothyroidism was corrected by supplementation with TH extract, Cyp7a1 protein is induced. Elevation of total bile salt pool size, enhanced fecal bile salt excretion and enlarged gallbladder volume is consistent with enhanced bile salt synthesis in these mice. Furthermore, liver-specific silencing of Tshr appears to result in elevation of Cyp7a1 protein and serum bile salts. Although an appropriate non-targeting siRNA control was lacking in the latter experiment, it suggests that endogenous TSH levels contribute to the regulation of bile salt synthesis via a direct effect on its hepatic receptor. In an elaborate set of in vitro experiments using human hepatoma cells, Song and colleagues went on to explore the molecular pathways underlying the Cyp7a1 repressive effect of TSH [6]. Having established that dysregulated Cyp7a1 expression in Tshr/ mice was apparently not due to alterations in the important FXR/Fgf15 regulatory axis [10,11], they observed enhanced hepatic levels of HNF4a and its target genes in knock-out animals, implying that TSH reduces HNF4a protein. This turned out to rely on activation of a PI3K-dependent pathway that led to enhanced expression of the nuclear, transcriptionally active form of SREBP2. It is currently unclear how activation of the
Journal of Hepatology 2015 vol. 62 j 1005–1007
Editorial TRH
Brain
Pituitary T3
TSH
TSH DIO2
TSHR
T4
HNF4α CYP7A1 SREBP2
TGR5
FXR
Bile salts
FGF19
FXR
SHP
Liver
FGFR4
Bile salts
FGF19
Bile salts Intestine Ileum enterocyte Fig. 1. Hepatic bile salt synthesis is controlled by multiple endocrine routes that target expression of the rate-determining enzyme (encoded by CYP7A1) in the biosynthetic pathway. Feedback inhibition of CYP7A1 expression by bile salts is mediated by the bile salt receptor FXR in ileum and liver. Activation of ileal FXR by bile salts results in release of endocrine-acting FGF19. Binding of this enterokine to its receptor (FGFR4) on the hepatocyte surface, activates signaling cascades that act to repress CYP7A1 in a SHP-dependent manner. Bile salts returning to the liver after a meal can activate hepatic FXR, resulting in induction of the transcriptional repressor SHP. The newly reported direct effect of TSH on the liver represses CYP7A1 by yet another mechanism involving induction of transcriptionally active SREBP2, which represses CYP7A1 by interfering with transcription of HNF4a. Bile salts may participate in the feedback loop that controls pituitary TSH release. This could be achieved by bile salt-mediated induction of pituitary DIO2 via the plasma membrane bile salt receptor TGR5. Enhanced DIO2 expression increases local formation of active thyroid hormone (T3), which represses release of TSH by the pituitary.
PI3K pathway is linked to the two sequential proteolytic cleavages of SREBP2 that are required to yield mature SREBP2 [12]. Putative binding sites for SREBP2 were predicted in the promoter region of (human) HNF4a, and TSH promoted recruitment of SREBP2 to this region. Moreover, a repressive effect of SREBP2 on human HNF4a promoter activity was observed in reporter assays. The aggregated mechanistic findings suggest that TSH represses Cyp7a1 via SREBP2-mediated interference with HNF4a transcription. Earlier animal studies by this group revealed that hepatic TSH signaling resulted in activation of SREBP1c, a key regulator of lipogenesis [12]. The concurrent activation of SREBP2, which stimulates cholesterol biosynthesis and interferes with subsequent conversion of cholesterol to bile salts, indicates that hepatic TSHR activation may impact on hepatic and serum lipid homeostasis. Moreover, the targeting of HNF4a, which controls diverse hepatic processes including glucose homeostasis, drug metabolism and cellular differentiation [9], implies that hepatic TSH signaling may have broader consequences. Further explorations are required to assess whether hepatic TSHR activation occurs at (patho)physiological levels of TSH. It will be interesting to learn whether hepatic TSHR expression, which in humans appears at least three orders of magnitude lower than expression in the thyroid gland (see e.g., supplementary materials in Ref. [13] or 1006
http://biogps.org/#goto=genereport&id=7253), is altered in liver disorders. Moreover, the contribution of adipose tissue, where Tshr signaling is engaged in regulation of lipolysis and inflammatory tone [2,14], should be considered in hepatic TSH action, as lipolytic products and cytokines are likely to have impact on hepatic processes. Studies employing tissue-specific Tshr/ mice could be helpful in this respect. Importantly, as well as challenging, is to address the physiological relevance of hepatic TSH action in humans. To assess whether TSH could contribute to regulation of bile salt synthesis in humans, Song and coworkers studied diurnal changes in circulating TSH, TH and bile salts in 15 volunteers receiving standardized meals for breakfast, lunch and dinner [6]. Postprandial changes in bile salts, peaking ca. 30–45 min after ingestion of each meal, were mirrored by opposite changes in TSH, with free T4 levels remaining constant throughout the 12 h study period. Levels of a serum marker for bile salt synthesis (C4) started to decline ca. 2 h after the first diurnal peak in TSH. It is reasonable to assume that CYP7A1 protein turnover must occur before transcriptional repression of the gene translates into a decline of serum C4 levels. Thus, the observed time lag appears compatible with, but is no direct evidence for, a role of TSH in repression of bile salt synthesis. Further studies with a more frequent blood sampling scheme, and simultaneous study of the intestinal
Journal of Hepatology 2015 vol. 62 j 1005–1007
JOURNAL OF HEPATOLOGY FXR/FGF19 axis that is considered the major pathway controlling bile salt synthesis in the postprandial state [10,11], could help to further delineate the respective contributions. The negative association between serum bile salts and TSH uncovered in the present study raises the intriguing question whether bile salts may actually control TSH levels. Pituitary release of TSH is subject to negative feedback control by locally produced T3 [15]. This requires the action of one of three iodothyronine deiodinases encoded by the DIO1–3 genes. These enzymes catalyze activation and inactivation of THs [2]. DIO2 has previously been identified as a bile salt-induced gene in brown adipose tissue and skeletal muscle [16], and catalyzes formation of active T3. The G-protein coupled receptor TGR5 (a.k.a. GPBAR1) confers induction of DIO2 by bile salts [16]. This plasma membrane bile salt receptor is broadly expressed, including in the hypothalamus and pituitary [17]. If bile salt-inducibility of DIO2 is maintained in these tissues, bile salts may regulate the negative feedback control of release of hypothalamic TSH-releasing hormone (TRH) and pituitary TSH [15]. TGR5 may thus link circulating bile salts to peripheral TH/TSH action, with elevation of bile salts resulting in diminished TSH levels and vice versa, as is observed in the human study of Song et al. [6]. Functional consequences related to this interaction can be expected in clinical conditions that are accompanied by elevation of systemic bile salts. For instance, bile salts are elevated, along with slightly lowered TSH, after Roux-en-Y gastric bypass [18,19]. In cholestatic liver disease, elevated serum bile salts may repress TSH release causing a subclinical reduction of TH synthesis. This may contribute to the enigmatic but devastating symptom of fatigue in patients with cholestatic liver disease (e.g. in primary biliary cirrhosis). In conclusion, direct hepatic TSH action is identified as a novel regulator of bile salt synthesis, although its modus operandi is likely to affect additional metabolic pathways in the liver as well. The importance of hepatic TSHR signaling in the complex network of regulatory inputs (including THs) that determines CYP7A1 expression, and its integration with the bile salt-induced FGF19 signaling pathway that is considered crucial for regulation of bile salt synthesis in the postprandial state, warrants further study. The mutual interaction between bile salts and TSH via a hypothalamic-pituitary circuit is another aspect that deserves further exploration, as well as rethinking the consequences of elevation of bile salts.
References [1] Brent GA. Mechanisms of thyroid hormone action. J Clin Invest 2012;122:3035–3043. [2] Davies TF, Ando T, Lin RY, Tomer Y, Latif R. Thyrotropin receptor-associated diseases: from adenomata to Graves disease. J Clin Invest 2005;115:1972–1983. [3] Zhang W, Tian LM, Han Y, Ma HY, Wang LC, Guo J, et al. Presence of thyrotropin receptor in hepatocytes: not a case of illegitimate transcription. J Cell Mol Med 2009;13:4636–4642. [4] Tian L, Song Y, Xing M, Zhang W, Ning G, Li X, et al. A novel role for thyroidstimulating hormone: up-regulation of hepatic 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase expression through the cyclic adenosine monophosphate/protein kinase A/cyclic adenosine monophosphate-responsive element binding protein pathway. Hepatology 2010;52:1401–1409. [5] Yan F, Wang Q, Lu M, Chen W, Song Y, Jing F, et al. Thyrotropin increases hepatic triglyceride content through upregulation of SREBP-1c activity. J Hepatol 2014;61:1358–1364. [6] Song Y, Xu C, Shao S, Liu J, Xing W, Xu J, et al. Thyroid-stimulating hormone (TSH) regulates hepatic bile acid homeostasis via SREBP-2/HNF-4alpha/ CYP7A1 axis. J Hepatol 2015;62:1171–1179. [7] Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 2003;72:137–174. [8] Chiang JY. Bile acids: regulation of synthesis. J Lipid Res 2009;50:1955–1966. [9] Gonzalez FJ. Regulation of hepatocyte nuclear factor 4 alpha-mediated transcription. Drug Metab Pharmacokinet 2008;23:2–7. [10] Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol 2014;11:55–67. [11] Kir S, Kliewer SA, Mangelsdorf DJ. Roles of FGF19 in liver metabolism. Cold Spring Harb Symp Quant Biol 2011;76:139–144. [12] Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997;89:331–340. [13] Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science 2015;347:1260419. [14] Gagnon A, Langille ML, Chaker S, Antunes TT, Durand J, Sorisky A. TSH signaling pathways that regulate MCP-1 in human differentiated adipocytes. Metabolism 2014;63:812–821. [15] Arrojo EDR, Fonseca TL, Werneck-de-Castro JP, Bianco AC. Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling. Biochim Biophys Acta 2013;1830:3956–3964. [16] Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006;439:484–489. [17] Duboc H, Tache Y, Hofmann AF. The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis 2014;46:302–312. [18] Jansen PL, van Werven J, Aarts E, Berends F, Janssen I, Stoker J, et al. Alterations of hormonally active fibroblast growth factors after Roux-en-Y gastric bypass surgery. Dig Dis 2011;29:48–51. [19] Patti ME, Houten SM, Bianco AC, Bernier R, Larsen PR, Holst JJ, et al. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism. Obesity 2009;17:1671–1677.
Conflict of interest The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Journal of Hepatology 2015 vol. 62 j 1005–1007
1007
Pituitary TSH controls bile salt synthesis Peter L.M. Jansen1,2,⇑, Frank G. Schaap1 1 Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO BOX 616, 6200 MD Maastricht, The Netherlands; 2Department of Gastroenterology and Hepatology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO BOX 616, 6200 MD Maastricht, The Netherlands
See Article, pages 1171–1179
Binding of thyroid-stimulating hormone (TSH, thyrotropin) to its receptor (TSHR) on the surface of thyroid follicular cells stimulates the formation and release of the active thyroid hormone (TH) triiodothyronine (T3), and its precursor, the prohormone thyroxine (T4) [1,2]. THs affect numerous biological processes through genomic as well as nongenomic actions involving nuclear TH receptors of the NR1A subfamily and specific members of the integrin family of plasma membrane receptors, respectively [1]. The liver is an important but somewhat undervalued target organ for TH action. Although most abundantly expressed in the thyroid gland, TSHR protein expression is detected amongst others in (pre)adipocytes, bone and kidney and this has led several groups to explore extrathyroidal actions of TSH [2]. In this issue, the group of Jiajun Zhao, which first reported on functional TSHR signaling in the liver [3–5], describes a direct effect of TSH on bile salt synthesis [6]. Bile salts act as emulsifiers of lipids, and as such are crucial for solubilization of biliary cholesterol and effective processing of diet-derived lipids. Levels of these biological detergents must be tightly controlled to prevent detrimental effects outside the gastrointestinal tract. In the liver, cholesterol is converted into bile salt conjugates by sequential action of at least 16 enzymes, and this pathway provides the major route for disposal of excess cholesterol [7]. Bile salt synthesis proceeds via either two routes, the classical pathway initiated by cholesterol-7a-hydroxylase (encoded by the CYP7A1 gene), and the acidic pathway initiated by enzymes that hydroxylate the side chain of cholesterol [7]. The classical pathway accounts for the bulk of newly synthesized
Keywords: Bile salts; Thyroid-stimulating hormone; CYP7A1; HNF4alpha. q DOI of original article: http://dx.doi.org/10.1016/j.jhep.2014.12.006. ⇑ Corresponding author. Address: Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, PO BOX 616, 6200 MD Maastricht, The Netherlands. E-mail address: [email protected] (P.L.M. Jansen). Abbreviations: TSH, thyroid-stimulating hormone; TSHR, TSH receptor; TH, thyroid hormone; NR, nuclear receptor; TRb, TH receptor b; HNF4a, hepatocyte nuclear factor 4a; FXR, farnesoid x receptor; FGF15/19, fibroblast growth factor 15/19; PI3K, phosphatidylinositol 3-kinase; SREBP, sterol regulatory elementbinding protein; TRH, TSH-releasing hormone; SHP, small heterodimer partner.
bile salts in rodents and human, with regulation exerted primarily at the level of CYP7A1 transcription [7,8]. The proximal CYP7A1 promoter contains overlapping binding sites for a number of positively and negatively acting transcription factors that together determine the overall transcriptional output. Members of the aforementioned family of nuclear receptors (NRs) that bind in this region include NR1A2/TRb, which mediates transcriptional regulation of CYP7A1 by THs, and NR2A1/HNF4a, a liver-enriched transcription factor that determines basal expression of CYP7A1 and a large number of other liverspecific genes [9]. It is this latter factor that is targeted by the newly uncovered hepatic action of TSH (Fig. 1). Using complementary approaches, Song et al. provide evidence that TSH is able to repress rodent Cyp7a1 expression in a manner independent of changes in total TH levels [6]. Firstly, in thyroidectomized rats with stable systemic levels of exogenously supplied T4, administration of recombinant TSH results in dosedependent lowering of Cyp7a1 activity and reduction of systemic and hepatic bile salt levels. Secondly, in Tshr/ mice in which hypothyroidism was corrected by supplementation with TH extract, Cyp7a1 protein is induced. Elevation of total bile salt pool size, enhanced fecal bile salt excretion and enlarged gallbladder volume is consistent with enhanced bile salt synthesis in these mice. Furthermore, liver-specific silencing of Tshr appears to result in elevation of Cyp7a1 protein and serum bile salts. Although an appropriate non-targeting siRNA control was lacking in the latter experiment, it suggests that endogenous TSH levels contribute to the regulation of bile salt synthesis via a direct effect on its hepatic receptor. In an elaborate set of in vitro experiments using human hepatoma cells, Song and colleagues went on to explore the molecular pathways underlying the Cyp7a1 repressive effect of TSH [6]. Having established that dysregulated Cyp7a1 expression in Tshr/ mice was apparently not due to alterations in the important FXR/Fgf15 regulatory axis [10,11], they observed enhanced hepatic levels of HNF4a and its target genes in knock-out animals, implying that TSH reduces HNF4a protein. This turned out to rely on activation of a PI3K-dependent pathway that led to enhanced expression of the nuclear, transcriptionally active form of SREBP2. It is currently unclear how activation of the
Journal of Hepatology 2015 vol. 62 j 1005–1007
Editorial TRH
Brain
Pituitary T3
TSH
TSH DIO2
TSHR
T4
HNF4α CYP7A1 SREBP2
TGR5
FXR
Bile salts
FGF19
FXR
SHP
Liver
FGFR4
Bile salts
FGF19
Bile salts Intestine Ileum enterocyte Fig. 1. Hepatic bile salt synthesis is controlled by multiple endocrine routes that target expression of the rate-determining enzyme (encoded by CYP7A1) in the biosynthetic pathway. Feedback inhibition of CYP7A1 expression by bile salts is mediated by the bile salt receptor FXR in ileum and liver. Activation of ileal FXR by bile salts results in release of endocrine-acting FGF19. Binding of this enterokine to its receptor (FGFR4) on the hepatocyte surface, activates signaling cascades that act to repress CYP7A1 in a SHP-dependent manner. Bile salts returning to the liver after a meal can activate hepatic FXR, resulting in induction of the transcriptional repressor SHP. The newly reported direct effect of TSH on the liver represses CYP7A1 by yet another mechanism involving induction of transcriptionally active SREBP2, which represses CYP7A1 by interfering with transcription of HNF4a. Bile salts may participate in the feedback loop that controls pituitary TSH release. This could be achieved by bile salt-mediated induction of pituitary DIO2 via the plasma membrane bile salt receptor TGR5. Enhanced DIO2 expression increases local formation of active thyroid hormone (T3), which represses release of TSH by the pituitary.
PI3K pathway is linked to the two sequential proteolytic cleavages of SREBP2 that are required to yield mature SREBP2 [12]. Putative binding sites for SREBP2 were predicted in the promoter region of (human) HNF4a, and TSH promoted recruitment of SREBP2 to this region. Moreover, a repressive effect of SREBP2 on human HNF4a promoter activity was observed in reporter assays. The aggregated mechanistic findings suggest that TSH represses Cyp7a1 via SREBP2-mediated interference with HNF4a transcription. Earlier animal studies by this group revealed that hepatic TSH signaling resulted in activation of SREBP1c, a key regulator of lipogenesis [12]. The concurrent activation of SREBP2, which stimulates cholesterol biosynthesis and interferes with subsequent conversion of cholesterol to bile salts, indicates that hepatic TSHR activation may impact on hepatic and serum lipid homeostasis. Moreover, the targeting of HNF4a, which controls diverse hepatic processes including glucose homeostasis, drug metabolism and cellular differentiation [9], implies that hepatic TSH signaling may have broader consequences. Further explorations are required to assess whether hepatic TSHR activation occurs at (patho)physiological levels of TSH. It will be interesting to learn whether hepatic TSHR expression, which in humans appears at least three orders of magnitude lower than expression in the thyroid gland (see e.g., supplementary materials in Ref. [13] or 1006
http://biogps.org/#goto=genereport&id=7253), is altered in liver disorders. Moreover, the contribution of adipose tissue, where Tshr signaling is engaged in regulation of lipolysis and inflammatory tone [2,14], should be considered in hepatic TSH action, as lipolytic products and cytokines are likely to have impact on hepatic processes. Studies employing tissue-specific Tshr/ mice could be helpful in this respect. Importantly, as well as challenging, is to address the physiological relevance of hepatic TSH action in humans. To assess whether TSH could contribute to regulation of bile salt synthesis in humans, Song and coworkers studied diurnal changes in circulating TSH, TH and bile salts in 15 volunteers receiving standardized meals for breakfast, lunch and dinner [6]. Postprandial changes in bile salts, peaking ca. 30–45 min after ingestion of each meal, were mirrored by opposite changes in TSH, with free T4 levels remaining constant throughout the 12 h study period. Levels of a serum marker for bile salt synthesis (C4) started to decline ca. 2 h after the first diurnal peak in TSH. It is reasonable to assume that CYP7A1 protein turnover must occur before transcriptional repression of the gene translates into a decline of serum C4 levels. Thus, the observed time lag appears compatible with, but is no direct evidence for, a role of TSH in repression of bile salt synthesis. Further studies with a more frequent blood sampling scheme, and simultaneous study of the intestinal
Journal of Hepatology 2015 vol. 62 j 1005–1007
JOURNAL OF HEPATOLOGY FXR/FGF19 axis that is considered the major pathway controlling bile salt synthesis in the postprandial state [10,11], could help to further delineate the respective contributions. The negative association between serum bile salts and TSH uncovered in the present study raises the intriguing question whether bile salts may actually control TSH levels. Pituitary release of TSH is subject to negative feedback control by locally produced T3 [15]. This requires the action of one of three iodothyronine deiodinases encoded by the DIO1–3 genes. These enzymes catalyze activation and inactivation of THs [2]. DIO2 has previously been identified as a bile salt-induced gene in brown adipose tissue and skeletal muscle [16], and catalyzes formation of active T3. The G-protein coupled receptor TGR5 (a.k.a. GPBAR1) confers induction of DIO2 by bile salts [16]. This plasma membrane bile salt receptor is broadly expressed, including in the hypothalamus and pituitary [17]. If bile salt-inducibility of DIO2 is maintained in these tissues, bile salts may regulate the negative feedback control of release of hypothalamic TSH-releasing hormone (TRH) and pituitary TSH [15]. TGR5 may thus link circulating bile salts to peripheral TH/TSH action, with elevation of bile salts resulting in diminished TSH levels and vice versa, as is observed in the human study of Song et al. [6]. Functional consequences related to this interaction can be expected in clinical conditions that are accompanied by elevation of systemic bile salts. For instance, bile salts are elevated, along with slightly lowered TSH, after Roux-en-Y gastric bypass [18,19]. In cholestatic liver disease, elevated serum bile salts may repress TSH release causing a subclinical reduction of TH synthesis. This may contribute to the enigmatic but devastating symptom of fatigue in patients with cholestatic liver disease (e.g. in primary biliary cirrhosis). In conclusion, direct hepatic TSH action is identified as a novel regulator of bile salt synthesis, although its modus operandi is likely to affect additional metabolic pathways in the liver as well. The importance of hepatic TSHR signaling in the complex network of regulatory inputs (including THs) that determines CYP7A1 expression, and its integration with the bile salt-induced FGF19 signaling pathway that is considered crucial for regulation of bile salt synthesis in the postprandial state, warrants further study. The mutual interaction between bile salts and TSH via a hypothalamic-pituitary circuit is another aspect that deserves further exploration, as well as rethinking the consequences of elevation of bile salts.
References [1] Brent GA. Mechanisms of thyroid hormone action. J Clin Invest 2012;122:3035–3043. [2] Davies TF, Ando T, Lin RY, Tomer Y, Latif R. Thyrotropin receptor-associated diseases: from adenomata to Graves disease. J Clin Invest 2005;115:1972–1983. [3] Zhang W, Tian LM, Han Y, Ma HY, Wang LC, Guo J, et al. Presence of thyrotropin receptor in hepatocytes: not a case of illegitimate transcription. J Cell Mol Med 2009;13:4636–4642. [4] Tian L, Song Y, Xing M, Zhang W, Ning G, Li X, et al. A novel role for thyroidstimulating hormone: up-regulation of hepatic 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase expression through the cyclic adenosine monophosphate/protein kinase A/cyclic adenosine monophosphate-responsive element binding protein pathway. Hepatology 2010;52:1401–1409. [5] Yan F, Wang Q, Lu M, Chen W, Song Y, Jing F, et al. Thyrotropin increases hepatic triglyceride content through upregulation of SREBP-1c activity. J Hepatol 2014;61:1358–1364. [6] Song Y, Xu C, Shao S, Liu J, Xing W, Xu J, et al. Thyroid-stimulating hormone (TSH) regulates hepatic bile acid homeostasis via SREBP-2/HNF-4alpha/ CYP7A1 axis. J Hepatol 2015;62:1171–1179. [7] Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem 2003;72:137–174. [8] Chiang JY. Bile acids: regulation of synthesis. J Lipid Res 2009;50:1955–1966. [9] Gonzalez FJ. Regulation of hepatocyte nuclear factor 4 alpha-mediated transcription. Drug Metab Pharmacokinet 2008;23:2–7. [10] Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol 2014;11:55–67. [11] Kir S, Kliewer SA, Mangelsdorf DJ. Roles of FGF19 in liver metabolism. Cold Spring Harb Symp Quant Biol 2011;76:139–144. [12] Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997;89:331–340. [13] Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science 2015;347:1260419. [14] Gagnon A, Langille ML, Chaker S, Antunes TT, Durand J, Sorisky A. TSH signaling pathways that regulate MCP-1 in human differentiated adipocytes. Metabolism 2014;63:812–821. [15] Arrojo EDR, Fonseca TL, Werneck-de-Castro JP, Bianco AC. Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling. Biochim Biophys Acta 2013;1830:3956–3964. [16] Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006;439:484–489. [17] Duboc H, Tache Y, Hofmann AF. The bile acid TGR5 membrane receptor: from basic research to clinical application. Dig Liver Dis 2014;46:302–312. [18] Jansen PL, van Werven J, Aarts E, Berends F, Janssen I, Stoker J, et al. Alterations of hormonally active fibroblast growth factors after Roux-en-Y gastric bypass surgery. Dig Dis 2011;29:48–51. [19] Patti ME, Houten SM, Bianco AC, Bernier R, Larsen PR, Holst JJ, et al. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism. Obesity 2009;17:1671–1677.
Conflict of interest The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
Journal of Hepatology 2015 vol. 62 j 1005–1007
1007
