Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone–binding globulin gene

Selva, David M.; Hogeveen, Kevin; Innis, Sheila M.; Hammond, Geoffrey L.

doi:10.1172/jci32249

Cited by 152 publications

(244 citation statements)

References 39 publications

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“…The possibility that expression of the human SHBG gene in the liver responds to an increased exposure to monosaccharides, rather than to insulin has been recently explored. Using transgenic mice expressing human SHBG transgenes and HepG2 human hepatoblastoma cells, Selva et al (2007) reported that glucose and fructose reduce human SHBG production by hepatocytes, via a down-regulation of hepatic HNF-4 levels in concert with parallel increases in cellular palmitate levels. Moreover, inhibition of lipogenesis prevented monosaccharide-induced down-regulation of HNF-4 and reduced the concomitant down-regulation of SHBG expression in HepG2 cells.…”

Section: Effects Of Insulin and Monosaccharidesmentioning

confidence: 99%

Sex hormone-binding globulin gene expression in the liver: Drugs and the metabolic syndrome

Pugeat

Nader

Hogeveen

et al. 2010

Molecular and Cellular Endocrinology

105

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. decrease SHBG expression by inducing lipogenesis, which reduces hepatic HNF-4α levels, a transcription factor that play a critical role in controlling the SHBG promoter. Interestingly, diminishing hepatic lipogenesis and free fatty acid liver biosynthesis also appear to be associated with the positive effects of thyroid hormones and PPARγ antagonists on SHBG expression. This mechanism provides a biological explanation for why SHBG is a sensitive biomarker of insulin resistance and the metabolic syndrome, and why low plasma SHBG levels are a risk factor for developing hyperglycemia and type 2 diabetes, especially in women. These important advances in our knowledge of the regulation of SHBG expression in the liver open new approaches for identifying and preventing metabolic disorder associated diseases early in life.

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Section: Effects Of Insulin and Monosaccharidesmentioning

confidence: 99%

Sex hormone-binding globulin gene expression in the liver: Drugs and the metabolic syndrome

Pugeat

Nader

Hogeveen

et al. 2010

Molecular and Cellular Endocrinology

105

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“…For experiments, HepG2 cells were cultured to 30-50% confluence prior to the addition of supplements: glucose (Sigma-Aldrich Canada Ltd), T 3 (Sigma-Aldrich), T 4 (Sigma-Aldrich) or etomoxir (Sigma-Aldrich), as indicated. Palmitate levels in HepG2 cells were determined as described previously (Selva et al 2007).…”

Section: Cell Culture Experimentsmentioning

confidence: 99%

“…Transient transfections of human SHBG promoterdriven luciferase reporter plasmids together with a pCMVlacZ control plasmid , Selva et al 2007 were performed using the HiPerfect Transfection Reagent (Qiagen). The siRNA experiments were carried out using HiPerfect Transfection Reagent together with either a control siRNA (catalog 1022076) or an hepatocyte nuclear factor-4a (HNF-4a) siRNA (catalog 00161546) obtained from Qiagen.…”

Section: Cell Culture Experimentsmentioning

confidence: 99%

“…Since thyroid hormones influence the metabolic state of the liver (Malik & Hodgson 2002) and because we have recently demonstrated that SHBG gene expression in hepatocytes is dynamically regulated by changes in their metabolic state (Selva et al 2007), we set out to determine whether thyroid hormoneinduced changes in the metabolic state of HepG2 cells and the liver could account for changes in SHBG expression.…”

Section: Introductionmentioning

confidence: 99%

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Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4α

Selva¹,

Hammond²

2009

Journal of Molecular Endocrinology

104

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Thyroid hormones increase hepatic sex hormone-binding globulin (SHBG) production, which is also regulated by hepatocyte nuclear factor-4a (HNF-4a) in response to changes in the metabolic state of the liver. Since the human SHBG promoter lacks a typical thyroid hormone response element, and because thyroid hormones influence metabolic state, we set out to determine whether thyroid hormones mediate SHBG expression indirectly via changes in HNF-4a levels in HepG2 human hepatoblastoma cells, and in the livers of transgenic mice that express a 4 . 3 kb human SHBG transgene under the control of its own 0 . 8 kb promoter sequence. Thyroid hormones (triiodothyronine (T 3 ) and thyroxine (T 4 )) increase SHBG accumulation in HepG2 cell culture medium over 5 days, and increase cellular SHBG mRNA levels. In addition, T 4 treatment of HepG2 cells for 5 days increased HNF-4a mRNA and HNF-4a levels in concert with decreased cellular palmitate levels. Plasma SHBG levels were also increased in mice expressing a human SHBG transgene after 5 days treatment with T 3 along with increased hepatic HNF-4a levels. In HepG2 cells, the human SHBG promoter failed to respond acutely (within 24 h) to T 4 treatment, but a 4-day pre-treatment with T 4 resulted in a robust response that was prevented by co-treatment with HNF-4a siRNA, or by blocking the b-oxidation of palmitate through co-treatment with the carnitine palmitoyltransferase I inhibitor, etomoxir. These data lead us to conclude that thyroid hormones increase SHBG production indirectly by increasing HNF-4a gene expression, and by reducing cellular palmitate levels that further contribute to increased HNF-4a levels in hepatocytes.

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“…This is especially the case in patients with low SHBG, which contributes per se to clinical hyperandrogenism. It is well documented that insulin resistance (45), liver lipogenesis and/or inflammation (46,47) decrease SHBG levels by a well-identified mechanism in the liver expression of SHBG gene. In addition, it is also documented that androgen excess reduces the inhibition of gonadotropin-releasing hormone pulse frequency normally exerted by progesterone, causing rapid LH pulse secretion and further maintaining or increasing ovarian androgen production (48).…”

Section: The Free-hormone Hypothesismentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE Hyperandrogenic states in women: pitfalls in laboratory diagnosis

Pugeat

Plotton

Perrière

et al. 2018

European Journal of Endocrinology

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Measuring total testosterone level is the first-line approach in assessing androgen excess in women.The main pitfalls in measuring testosterone relate to its low concentration and to the structural similarity between circulating androgens and testosterone, requiring accurate techniques with high specificity and sensitivity. These goals can be achieved by immunoassay using a specific antitestosterone monoclonal antibody, ideally after an extraction step. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) will be commonly used for measuring testosterone, providing optimal accuracy with a low limit of detection. Yet, the pitfalls of these two techniques are well identified and must be recognized and systematically addressed. In general, laboratories using direct testosterone immunoassay and mass spectrometry need to operate within a quality framework and be actively engaged in external quality control processes and standardization, so as to ensure appropriate interpretation irrespective of the particular laboratory. Circulating testosterone is strongly bound to sex-hormone binding-globulin (SHBG), and SHBG levels are typically low in overweight hyperandrogenic patients. Thus, low SHBG may decrease circulating testosterone to normal values, which will mask androgen excess status. One way to avoid this pitfall, awaiting direct free-testosterone assays that are yet to be developed, is to measure SHBG and calculate free testosterone. A few other pitfalls will be discussed in this review, including those of adrenal androgen exploration, with the aim of helping clinicians to better handle laboratory investigation of androgen excess disorders in women.

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Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone–binding globulin gene

Cited by 152 publications

References 39 publications

Sex hormone-binding globulin gene expression in the liver: Drugs and the metabolic syndrome

Sex hormone-binding globulin gene expression in the liver: Drugs and the metabolic syndrome

Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4α

MANAGEMENT OF ENDOCRINE DISEASE Hyperandrogenic states in women: pitfalls in laboratory diagnosis

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