RESUMEN
Effectively treating metabolic syndrome and its progression to type 2 diabetes, steatohepatitis and cardiovascular disease remain a major clinical challenge. The use of a novel engineered molecule that combines thyroid hormone and glucagon to target liver and adipose tissue might provide a new 'magic bullet' with exciting future prospects.
Asunto(s)
Glucagón/uso terapéutico , Hormonas/uso terapéutico , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/metabolismo , Triyodotironina/uso terapéutico , Animales , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/prevención & control , Hígado Graso/etiología , Hígado Graso/prevención & control , Glucagón/química , Glucagón/metabolismo , Hormonas/química , Hormonas/metabolismo , Humanos , Síndrome Metabólico/complicaciones , Triyodotironina/química , Triyodotironina/metabolismoRESUMEN
OBJECTIVE: Hepcidin reduces iron absorption by binding to the intestinal iron transporter ferroportin, thereby causing its degradation. Although short-term administration of testosterone or growth hormone (GH) has been reported to decrease circulating hepcidin levels, little is known about how hepcidin is influenced in human endocrine conditions associated with anemia. RESEARCH DESIGN AND METHODS: We used a sensitive and specific dual-monoclonal antibody sandwich immunoassay to measure hepcidin-25 in patients (a) during initiation of in vitro fertilization when endogenous estrogens were elevated vs. suppressed, (b) with GH deficiency before and after 12 months substitution treatment, (c) with hyperthyroidism before and after normalization, and (d) with hyperprolactinemia before and after six months of treatment with a dopamine agonist. RESULTS: In response to a marked stimulation of endogenous estrogen production, median hepcidin levels decreased from 4.85 to 1.43 ng/mL (p < 0.01). Hyperthyroidism, hyperprolactinemia, or GH substitution to GH-deficient patients did not influence serum hepcidin-25 levels. CONCLUSIONS: In humans, gonadotropin-stimulated endogenous estrogen markedly decreases circulating hepcidin-25 levels. No clear and stable correlation between iron biomarkers and hepcidin-25 was seen before or after treatment of hyperthyroidism, hyperprolactinemia or growth hormone deficiency.
Asunto(s)
Anemia/sangre , Estrógenos/fisiología , Hepcidinas/sangre , Adolescente , Adulto , Anciano , Anemia/metabolismo , Proteína C-Reactiva/biosíntesis , Proteína C-Reactiva/metabolismo , Agonistas de Dopamina/química , Femenino , Ferritinas/biosíntesis , Ferritinas/metabolismo , Fertilización In Vitro , Hormona de Crecimiento Humana/deficiencia , Hormona de Crecimiento Humana/metabolismo , Humanos , Hiperprolactinemia/complicaciones , Hipertiroidismo/complicaciones , Inmunoensayo , Hierro/metabolismo , Masculino , Persona de Mediana Edad , Prolactinoma/sangre , Transferrina/biosíntesis , Transferrina/metabolismo , Adulto JovenRESUMEN
High endogenous production of, or treatment with muricholic bile acids, strongly reduces the absorption of cholesterol. Mice abundant in muricholic bile acids may therefore display an increased resistance against dietary induced weight gain, steatosis, and glucose intolerance due to an anticipated general reduction in lipid absorption. To test this hypothesis, mice deficient in steroid 12-alpha hydroxylase (Cyp8b1-/-) and therefore abundant in muricholic acids were monitored for 11 weeks while fed a high fat diet. Food intake and body and liver weights were determined, and lipids in liver, serum and feces were measured. Further, responses during oral glucose and intraperitoneal insulin tolerance tests were evaluated. On the high fat diet, Cyp8b1-/- mice displayed less weight gain compared to wildtype littermates (Cyp8b1+/+). In addition, liver enlargement with steatosis and increases in serum LDL-cholesterol were strongly attenuated in Cyp8b1-/- mice on high fat diet. Fecal excretion of cholesterol was increased and there was a strong trend for doubled fecal excretion of free fatty acids, while excretion of triglycerides was unaltered, indicating dampened lipid absorption. On high fat diet, Cyp8b1-/- mice also presented lower serum glucose levels in response to oral glucose gavage or to intraperitoneal insulin injection compared to Cyp8b1+/+. In conclusion, following exposure to a high fat diet, Cyp8b1-/- mice are more resistant against weight gain, steatosis, and to glucose intolerance than Cyp8b1+/+ mice. Reduced lipid absorption may in part explain these findings. Overall, the results suggest that muricholic bile acids may be beneficial against the metabolic syndrome.
Asunto(s)
Ácidos Cólicos/metabolismo , Hígado Graso/metabolismo , Hígado Graso/patología , Glucosa/metabolismo , Hígado/patología , Animales , Colesterol/metabolismo , Dieta Alta en Grasa/efectos adversos , Hígado Graso/genética , Femenino , Eliminación de Gen , Intolerancia a la Glucosa/genética , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/patología , Hígado/metabolismo , Masculino , Ratones , Esteroide 12-alfa-Hidroxilasa/genética , Aumento de PesoRESUMEN
BACKGROUND: Bile acid synthesis has been considered a prototype for how a physiological process is controlled by end product feedback inhibition. By this feedback inhibition, bile acid concentrations are kept within safe ranges. However, careful examination of published rodent data strongly suggests that bile acid synthesis is also under potent positive feedback control by hydrophilic bile acids. KEY MESSAGES: Current concepts on the regulation of bile acid synthesis are derived from mouse models. Recent data have shown that mice have farnesoid X receptor (FXR) antagonistic bile acids capable of quenching responses elicited by FXR agonistic bile acids. This is important to recognize to understand the regulation of bile acid synthesis in the mouse, and in particular to clarify if mouse model findings are valid also in the human situation. CONCLUSIONS: In addition to classic end product feedback inhibition, regulation of bile acid synthesis in the mouse largely appears also to be driven by changes in hepatic levels of murine bile acids such as α- and ß-muricholic acids. This has not been previously recognized. Stimulated bile acid synthesis or induction of the apical sodium-dependent bile acid transporter in the intestine, increase the availability of chenodeoxycholic acid in the liver, thereby promoting hepatic conversion of this bile acid into muricholic acids. Recognition of these mechanisms is essential for understanding the regulation of bile acid synthesis in the mouse, and for our awareness of important species differences in the regulation of bile acid synthesis in mice and humans.
Asunto(s)
Ácidos y Sales Biliares/biosíntesis , Retroalimentación Fisiológica , Transportadores de Anión Orgánico Sodio-Dependiente/metabolismo , Receptores Citoplasmáticos y Nucleares , Simportadores/metabolismo , Ampicilina/farmacología , Animales , Ácido Quenodesoxicólico/biosíntesis , Ácido Quenodesoxicólico/farmacología , Colesterol 7-alfa-Hidroxilasa/genética , Ácido Cólico/farmacología , Ácidos Cólicos/metabolismo , Ácido Desoxicólico/farmacología , Modelos Animales de Enfermedad , Retroalimentación Fisiológica/efectos de los fármacos , Humanos , Ratones , Ratones Noqueados , Fenotipo , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidoresRESUMEN
Reduced plasma LDL-cholesterol is a hallmark of hyperthyroidism and is caused by transcriptional stimulation of LDL receptors in the liver. Here, we investigated whether thyroid hormone (TH) actions involve other mechanisms that may also account for the reduction in LDL-cholesterol, including effects on proprotein convertase subtilisin/kexin type 9 (PCSK9) and bile acid synthesis. Twenty hyperthyroid patients were studied before and after clinical normalization, and the responses to hyperthyroidism were compared with those in 14 healthy individuals after 14 days of treatment with the liver-selective TH analog eprotirome. Both hyperthyroidism and eprotirome treatment reduced circulating PCSK9, lipoprotein cholesterol, apoB and AI, and lipoprotein(a), while cholesterol synthesis was stable. Hyperthyroidism, but not eprotirome treatment, markedly increased bile acid synthesis and reduced fibroblast growth factor (FGF) 19 and dietary cholesterol absorption. Eprotirome treatment, but not hyperthyroidism, reduced plasma triglycerides. Neither hyperthyroidism nor eprotirome treatment altered insulin, glucose, or FGF21 levels. TH reduces circulating PSCK9, thereby likely contributing to lower plasma LDL-cholesterol in hyperthyroidism. TH also stimulates bile acid synthesis, although this response is not critical for its LDL-lowering effect.
Asunto(s)
Ácidos y Sales Biliares/biosíntesis , Proproteína Convertasas/sangre , Serina Endopeptidasas/sangre , Hormonas Tiroideas/metabolismo , Adolescente , Adulto , Anciano , Anilidas/farmacología , Apolipoproteínas B/sangre , Ácidos y Sales Biliares/sangre , Ácidos y Sales Biliares/química , Glucemia/metabolismo , Composición Corporal/efectos de los fármacos , Colesterol/sangre , Femenino , Factor 9 de Crecimiento de Fibroblastos/sangre , Factores de Crecimiento de Fibroblastos/sangre , Humanos , Hipertiroidismo/sangre , Hipertiroidismo/enzimología , Hipertiroidismo/metabolismo , Insulina/sangre , Absorción Intestinal/efectos de los fármacos , Lipoproteína(a)/sangre , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Proproteína Convertasa 9 , Receptores de Hormona Tiroidea/agonistas , Adulto JovenRESUMEN
UNLABELLED: Secretion of cholesterol into bile is important for the elimination of cholesterol from the body. Thyroid hormone (TH) increases biliary cholesterol secretion and hepatic gene expression of adenosine triphosphate (ATP)-binding cassette, subfamily G (WHITE), member 5 (ABCG5) and ATP-binding cassette, subfamily G (WHITE), member 8 (ABCG8), two half-transporters that act as a heterodimeric complex promoting sterol secretion. In addition, nuclear liver x receptor-alpha (LXRa), also regulated by TH, induces gene expression of ABCG5/G8. We here investigated if the TH-induced stimulation of biliary cholesterol secretion is mediated by the ABCG5/G8 complex in vivo, and if so, whether LXRa is involved. Mice homozygous for disruption of Abcg5 (Abcg5(-/-) ) or Lxra (Lxra(-/-) ) and their wild-type counterparts were treated with triiodothyronine (T3) for 14 days and compared to untreated mice of corresponding genetic backgrounds. Bile was collected by gallbladder cannulation, and liver samples were analyzed for gene expression levels. Basal biliary cholesterol secretion in Abcg5(-/-) mice was 72% lower than in Abcg5(+/+) mice. T3 treatment increased cholesterol secretion 3.1-fold in Abcg5(+/+) mice, whereas this response was severely blunted in Abcg5(-/-) mice. In contrast, biliary cholesterol secretion in T3-treated Lxra(+/+) and Lxra(-/-) mice was increased 3.5- and 2.6-fold, respectively, and did not differ significantly. CONCLUSIONS: TH-induced secretion of cholesterol into bile is largely dependent on an intact ABCG5/G8 transporter complex, whereas LXRa is not critical for this effect.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Bilis/metabolismo , Colesterol/metabolismo , Expresión Génica/efectos de los fármacos , Lipoproteínas/genética , Hígado/metabolismo , Receptores Nucleares Huérfanos/genética , ARN/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5 , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8 , Transportadoras de Casetes de Unión a ATP/efectos de los fármacos , Análisis de Varianza , Animales , Ácidos y Sales Biliares/metabolismo , Colesterol 7-alfa-Hidroxilasa/genética , Homocigoto , Hidroximetilglutaril-CoA Reductasas/genética , Lipoproteínas/efectos de los fármacos , Receptores X del Hígado , Masculino , Ratones , Receptores Nucleares Huérfanos/efectos de los fármacos , Fosfolípidos/análisis , Receptores de LDL/genética , Triyodotironina/farmacologíaRESUMEN
BACKGROUND & AIMS: Hypopituitarism is associated with dyslipidemia, and feeding hypophysectomized rats cholesterol induces severe hypercholesterolemia. This study aimed to unravel further how hypophysectomy alters cholesterol and bile acid metabolism. METHODS: Intact and hypophysectomized rats were studied during challenge with dietary cholesterol and ezetimibe and upon hormonal substitution with growth hormone, cortisone, and thyroid hormone. RESULTS: Five findings were established in hypophysectomized rats: (1) The intestinal absorption of cholesterol is doubled. (2) Treatment with ezetimibe abolishes the increases in serum and liver cholesterol. (3) Only thyroid hormone treatment normalizes the increased absorption of cholesterol. (4) The intestinal gene expression of cholesterol transporters NPC1L1 and ABCG5/G8 is unaltered, whereas the hepatic expression of ABCG5/G8 is diminished but strongly stimulated by thyroid hormone. The latter mechanism was supported by measurements of biliary cholesterol and of fecal neutral steroids. (5) The reduced hepatic expression of ABCG5/G8 and Cyp7a1 was normalized by cholesterol feeding, suggesting that other nonestablished mechanisms under pituitary control are important to maintain rats resistant to dietary cholesterol. CONCLUSIONS: The intestinal absorption of dietary cholesterol is under pituitary control largely exerted by thyroid hormone. Hepatic secretion of cholesterol and ABCG5/G8 expression are strongly stimulated in hypophysectomized rats during treatment with thyroid hormone.