[Show abstract][Hide abstract] ABSTRACT: A 73-year-old woman was admitted due to weight loss and generalized malaise. The basal levels of all the anterior pituitary hormones, except for prolactin, were reduced. However, they were all elevated in response to exogenous hypothalamic hormones. After starting hydrocortisone replacement, the patient had polyuria of >5,000 mL/day. T1-weighted MRI depicted a low signal of an oval mass in the sella turcica and an iso-intense signal of another mass at the pituitary stalk. These findings indicate a hypothalamic type of hypopituitarism and masked central diabetes insipidus which possibly derived from the atypical occupation of Rathke's cleft cyst at the pituitary stalk.
[Show abstract][Hide abstract] ABSTRACT: There is evidence that betatrophin, a hormone derived from adipose tissue and liver, affects the proliferation of pancreatic beta cells in mice. The aim of this study was to examine circulating betatrophin concentrations in Japanese healthy controls and patients with type 1 and type 2 diabetes. A total of 76 subjects (12 healthy controls, 34 type 1 diabetes, 30 type 2 diabetes) were enrolled in the study. Circulating betatrophin was measured with an ELISA kit and clinical parameters related to betatrophin were analyzed statistically. Circulating betatrophin (Log transformed) was significantly increased in patients with diabetes compared with healthy subjects (healthy controls, 2.29 ± 0.51; type 1 diabetes, 2.94 ± 0.44; type 2 diabetes, 3.17 ± 0.18; p<0.001, 4.1 to 5.4 times in pg/mL order). Age, HbA1c, fasting plasma glucose and Log triglyceride were strongly associated with Log betatrophin in all subjects (n=76) in correlation analysis. In type 1 diabetes, there was a correlation between Log betatrophin and Log CPR. These results provide the first evidence that circulating betatrophin is significantly elevated in Japanese patients with diabetes. The findings of this pilot study also suggest a possibility of association between the level of betatrophin and the levels of glucose and triglycerides.
Full-text · Article · Mar 2015 · Endocrine Journal
[Show abstract][Hide abstract] ABSTRACT: A 68-year-old woman was admitted to determine the pathogenesis of weight loss and polyuria. Physical findings on admission showed BMI of 20.9, blood pressure of 147/69 mmHg, and that she had ciliac, axillar and pubic hair loss. Laboratory findings showed that plasma adrenocorticotropic hormone (ACTH) was 4.6 pg/mL with serum cortisol of 1.2 µg/dL. Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were markedly reduced. Serum growth hormone (GH) and insulin growth factor (IGF)-1 were 0.054 ng/mL and 25 ng/mL, respectively. Serum prolactin was as high as 85.6 ng/mL. The levels of all the pituitary hormones were elevated in response to a mixture of exogenous corticotrophin-releasing hormone (CRH), luteinizing hormone-releasing hormone (LH-RH), thyrotropin-releasing hormone (TRH), and growth hormone-releasing hormone (GRH). However, there was no response of ACTH and GH release to insulin-induced hypoglycemia and no response of LH and FSH release to clomiphene. Urine volume was more than 4,000 mL, with low urine osmolality of 134 mmol/kg. Plasma arginine vasopressin (AVP) was 0.8 pg/mL. There was no increase in urine osmolality and plasma AVP in response to 5% hypertonic saline load. Magnetic resonance imaging revealed Rathke's cleft cyst at the pituitary stalk level, but there was no abnormal finding in the hypothalamus. These findings indicate central diabetes insipidus and hypothalamic type of hypopituitarism, resulting from the atypical location of Rathke's cleft cyst.
No preview · Article · Jan 2012 · Internal Medicine
[Show abstract][Hide abstract] ABSTRACT: A 38-year-old man was admitted for evaluation of Cushing's syndrome. Physical findings showed swelling of the face, and hypertension, but not Cushingoid stigmata. Laboratory data revealed serum cortisol level of 34.1 µg/dL and plasma ACTH of 140 pg/mL. Overnight administration of 1 and 8 mg dexamethasone did not suppress plasma ACTH or serum cortisol. Chest X-ray showed a mass at the upper-anterior quadrant of the mediastinum, and chest CT scan revealed a heterogenous tumor of approximately 60 mm in diameter, which infiltrated into the superior vena cava and ascending aorta, and caused superior vena cava syndrome. The tumor was resected. Histological examination indicated large cell neuroendocrine carcinoma of the thymus and positive immunoreactivity for ACTH. Ten days after the operation, the plasma ACTH decreased as low as 13.7 pg/mL. The present study indicates that large cell neuroendocrine carcinoma of the thymus can cause superior vena cava syndrome and ectopic ACTH syndrome.
No preview · Article · Jan 2011 · Internal Medicine
[Show abstract][Hide abstract] ABSTRACT: We demonstrated a rare case of bilateral aldosteronoma accompanied by secondary aldosteronism in a 37-year-old man with chronic renal failure on hemodialysis. He initially developed immunoglobulin A nephropathy at 11 years old, and had been treated with hemodialysis since the age of 17 years. His blood pressure was 110/68 mmHg, and no other abnormal findings were detected. Laboratory findings revealed that serum potassium was 3.9 mmol/L; plasma renin activity, 4.8 ng/ml/h and plasma aldosterone, 19,000 pg/mL. Abdominal computed tomography revealed bilateral adrenocortical tumors, measuring 34 and 40 mm in diameter in right and left tumors, respectively. (131)I-Adosterol scintigram showed bilateral accumulation. Left adrenalectomy was performed under laparoscopy. The tumor was encapsulated and well-circumscribed. The majority of the tumor was composed of a dark-brown portion admixed with sporadic foci of golden-yellow portions. Hyaline degeneration was detected in its central portion. The tumor was composed of clear cortical cells in viable portions. Tumor cells demonstrated immunoreactivity for the cholesterol side-chain cleavage enzyme, 3beta-hydroxysteroid dehydrogenase (3beta-HSD II) and 21-hydroxylase, but not 17 alpha-hydroxylase. In the adjacent non-neoplastic adrenals, 3 beta-HSD II was markedly present in the hyperplastic glomerulosa zone. These findings suggest that the presence of secondary aldosteronism, which is closely related to the conditions of chronic renal failure on hemodialysis, eventually promoted the development of bilateral aldosteronoma from the zona glomerulosa hyperplasia.
No preview · Article · Jan 2010 · Internal Medicine
[Show abstract][Hide abstract] ABSTRACT: A 62 year-old man was admitted to determine the pathogenesis of his hypoglycemia. He was unconscious and his plasma glucose level was 26 mg/dL. When he was 31 years old, he had a traffic accident and was unconscious for several days. Physical findings on admittance showed that the patient's BMI was 17.8 and blood pressure, 114/70 mmHg. He was alert. He had a hypogonadal face with a lack of beard, and he had an atrophic testis with a volume of 1 to 2 ml. Laboratory findings showed that his fasting plasma glucose was 73 mg/dL; serum sodium, 133 mmol/l; potassium, 4.1 mmol/l; serum insulin, less than 1.0 muU/ml.; plasma ACTH, 45.8 pg/ml; serum cortisol, 5.2 microg/dL; and free cortisol urinary excretion, less than 4.5 microg/day; serum LH, 0.8 mIU/ml; serum testosterone, less than 0.05 ng/ml; serum TSH, 2.0 uIU/ml; free T(4), 0.7 ng/dL; free T(3), 1.5 pg/ml; and serum prolactin, 29.0 ng/ml. The levels of all the pituitary hormones were elevated in response to a mixture of exogenous corticotrophin-releasing hormone (CRH), luteinizing hormone-releasing hormone (LH-RH), thyrotropin-releasing hormone (TRH), and growth hormone-releasing hormone (GRH). However, there was no increased secretion of adrenocorticotropic hormone (ACTH) in response to hypoglycemia (induced by the administration of insulin) and there was no increased secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in response to the administration of clomiphene. Magnetic resonance imaging revealed an atrophied pituitary gland with an empty sella, but there were no abnormal findings of the hypothalamus. Hydrocortisone replacement at a dosage of 20 mg/day increased the patient's plasma glucose from 73 to 100 mg/dL and his serum sodium from 133 to 138 mmol/l. These findings therefore indicate a partial impairment in hypothalamic hormone release, resulting from a traumatic brain injury that the patient had received 31 years ago.
No preview · Article · Aug 2009 · Endocrine Journal
[Show abstract][Hide abstract] ABSTRACT: Regulation of delayed rectifier-type K(+) channels (Kv-channels) by glucose was studied in rat pancreatic beta-cells. The Kv-channel current was increased in amplitudes by increasing glucose concentration from 2.8 to 16.6mM, while it was decreased by 2.8mM glucose in a reversible manner (down-regulation) in both perforated and conventional whole-cell modes. The current was decreased by FCCP, intrapipette 0mM ATP or AMPPNP. Glyceraldehyde, pyruvic acid, 2-ketoisocaproic acid, and 10mM MgATP prevented the down-regulation induced by 2.8mM or less glucose. The residual current after treatment with Kv2.1-specific blocker, guangxitoxin-1E, was unchanged by lowering or increasing glucose concentration. We conclude that glucose metabolism regulates Kv2.1 channels in rats beta-cells via altering MgATP levels.
[Show abstract][Hide abstract] ABSTRACT: Neovascularization is an important event in proliferative diabetic retinopathy (PDR), where various secretory proteins including multiple growth factors are considered to be involved in this process. We searched for secretory proteins expressed in a surgical specimen obtained from the eyes of patients with PDR.
We developed the oligo-cap signal sequence trap (SST) strategy which enables us to screen for secretory or membrane proteins from a minimal starting material. Using this method, we were able to screen a cDNA library constructed from a surgical specimen obtained from the eyes of the patients with PDR.
Majority of the cloned cDNAs turned out to encode secreted protein acidic and rich in cystein (SPARC), strongly suggesting that SPARC is highly expressed in PDR. Analysis of vitreous fluid from various patients has shown that the concentration of SPARC protein is increased in patients with PDR. Furthermore, subretinal injection of recombinant SPARC adenovirus induced PDR-like changes in the rat eye.
Our results strongly suggested that SPARC is involved in the development of diabetic retinopathy (DR).
No preview · Article · May 2009 · Journal of atherosclerosis and thrombosis
[Show abstract][Hide abstract] ABSTRACT: The present study was undertaken to determine retinol-binding protein 4 (RBP4) levels in subjects with diabetic nephropathy. A total of 149 type 2 diabetic subjects and 19 control subjects were enrolled. Serum levels of RBP4 were measured by a method of ELISA. Serum RBP4 levels were significantly greater in the subjects with type 2 diabetes mellitus than the controls (70.5 +/- 35.3 vs. 40.1 +/- 13.0 microg/ml, mean +/- SD, p<0.01). Serum RBP4 levels were gradually increased according to the progression of diabetic nephropathy (p value in trend test: <0.001). Its elevation was significantly greater in the diabetic subjects with stages 1, 3B and 4 than the control subjects (Stage 1: 64.6 +/- 29.7, Stage 3B: 123.3 +/- 71.8, Stage 4: 91.4 +/- 33.8 vs. Control: 40.1 +/- 13.0 microg/ml, p<0.01). Similar results were obtained in the subjects based on the amount of albuminuria (Normo-: 64.6 +/- 29.7, Micro-: 63.7 +/- 29.4, and Marcoalbuminuria: 90.3 +/- 44.6 microg/ml, p <0.001). Serum RBP4 levels had a positive correlation with serum creatinine levels(r = 0.377, p<0.001), and a negative correlation with 1/creatinine (r = -0.420, p<0.001). Also, there was a negative correlation between serum RBP4 and the estimated glomerular filtration rate(r = -0.436, p<0.001). Multiple regression analysis showed that estimated glomerular filtration rate was an independent determinant for increased serum RBP4 levels. There was no difference in serum RBP4 levels between the advanced nephropathy with and without macrovascular diseases. These results indicate an increase in serum RBP4 levels in the type 2 diabetic subjects, particularly complicated with advanced renal impairment.
No preview · Article · Dec 2008 · Endocrine Journal
[Show abstract][Hide abstract] ABSTRACT: Both adipocyte hyperplasia and hypertrophy are determinant factors for adipocyte differentiation during the development of
obesity. p21WAF1/CIP1, a cyclin-dependent kinase inhibitor, is induced during adipocyte differentiation; however, its precise contribution to this
process is unknown. Using both in vitro and in vivo systems, we show that p21 is crucial for maintaining adipocyte hypertrophy and obesity-induced insulin resistance. The absence
of p21 in 3T3-L1 fibroblasts by RNA-mediated interference knockdown or in embryonic fibroblasts from p21-/- mice impaired adipocyte differentiation, resulting in smaller adipocytes. Despite normal adipose tissue mass on a normal
diet, p21-/- mice fed high energy diets had reduced adipose tissue mass and adipocyte size accompanied by a marked improvement in insulin
sensitivity. Knockdown of p21 in enlarged epididymal fat of diet-induced obese mice and also in fully differentiated 3T3-L1
adipocytes caused vigorous apoptosis by activating p53. Thus, p21 is involved in both adipocyte differentiation and in protecting
hypertrophied adipocytes against apoptosis. Via both of these mechanisms, p21 promotes adipose tissue expansion during high
fat diet feeding, leading to increased downstream pathophysiological consequences such as insulin resistance.
Full-text · Article · Aug 2008 · Journal of Biological Chemistry
[Show abstract][Hide abstract] ABSTRACT: Insulin resistance is often associated with obesity and can precipitate type 2 diabetes. To date, most known approaches that improve insulin resistance must be preceded by the amelioration of obesity and hepatosteatosis. Here, we show that this provision is not mandatory; insulin resistance and hyperglycemia are improved by the modification of hepatic fatty acid composition, even in the presence of persistent obesity and hepatosteatosis. Mice deficient for Elovl6, the gene encoding the elongase that catalyzes the conversion of palmitate to stearate, were generated and shown to become obese and develop hepatosteatosis when fed a high-fat diet or mated to leptin-deficient ob/ob mice. However, they showed marked protection from hyperinsulinemia, hyperglycemia and hyperleptinemia. Amelioration of insulin resistance was associated with restoration of hepatic insulin receptor substrate-2 and suppression of hepatic protein kinase C epsilon activity resulting in restoration of Akt phosphorylation. Collectively, these data show that hepatic fatty acid composition is a new determinant for insulin sensitivity that acts independently of cellular energy balance and stress. Inhibition of this elongase could be a new therapeutic approach for ameliorating insulin resistance, diabetes and cardiovascular risks, even in the presence of a continuing state of obesity.
[Show abstract][Hide abstract] ABSTRACT: Sterol regulatory element-binding protein (SREBP)-1a is a unique membrane-bound transcription factor highly expressed in actively growing cells and involved in the biosynthesis of cholesterol, fatty acids, and phospholipids. Because mammalian cells need to synthesize membrane lipids for cell replication, the functional relevance of SREBP-1a in cell proliferation has been considered a biological adaptation. However, the effect of this potent lipid-synthesis activator on cell growth has never been explored. Here, we show that induction of nuclear SREBP-1a, but not SREBP-2, completely inhibited cell growth in inducible Chinese hamster ovary (CHO) cell lines. Growth inhibition occurred through G(1) cell-cycle arrest, which is observed in various cell types with transient expression of nuclear SREBP-1a. SREBP-1a caused the accumulation of cyclin-dependent kinase (cdk) inhibitors such as p27, p21, and p16, leading to reduced cdk2 and cdk4 activities and hypophosphorylation of Rb protein. In contrast to transactivation of p21, SREBP-1a activated p27 by enhancing stabilization of the protein through inhibition of SKP2 and KPC1. In vivo, SREBP-1a-expressing livers of transgenic mice exhibited impaired regeneration after partial hepatectomy. SREBP-1-null mouse embryonic fibroblasts had a higher cell proliferation rate than wild-type cells. The unexpected cell growth-inhibitory role of SREBP-1a provides a new paradigm to link lipid synthesis and cell growth.
[Show abstract][Hide abstract] ABSTRACT: A number of adipocytokines have been suggested to be involved in the disruption of glucose metabolism, and also in the development of various diabetic complications. We attempted to identify and analyze additional adipocytokines, to better understanding the roles of adipocytes and adipocytokines.
An oligo-capping signal sequence trap, developed in our laboratory for screening the cDNAs of secretory proteins, was used to sreen cDNAs expressed in mouse white adipose tissue. Profiles of the genes identified in mice and cultured cells were further investigated by northern blotting and luciferase assay.
A cDNA fragment of interferon-stimulated gene 12b (ISG12b) was obtained in the search. A northern blot analysis revealed ISG12b to be highly expressed in white adipose tissue. Interferon alpha (IFNalpha) was shown to induce ISG12b expression in the adipose tissue of BL6 mice in vivo, and also in a 3T3-L1 preadipocyte cell line in vitro. The level of ISG12b was higher in mature adipocytes than in preadipocytes. A promoter analysis demonstrated that the 369bp upstream from the transcription initiation site of ISG12b mRNA contain strong promoter activity, and the interferon-stimulated response elements (ISREs) were not present within the 5593bp upstream region.
ISG12b is an additional candidate for a adipocytokine induced to express in adipose tissue by interferon.
No preview · Article · Sep 2007 · Journal of atherosclerosis and thrombosis
[Show abstract][Hide abstract] ABSTRACT: Sterol regulatory element-binding protein (SREBP)-1c is a transcription factor that controls synthesis of fatty acids and
triglycerides in the liver and is highly regulated by nutrition and hormones. In the current studies we show that protein
kinase A (PKA), a mediator of glucagon/cAMP, a fasting signaling, suppresses SREBP-1c by modulating the activity of liver
X receptor α (LXRα), a dominant activator of SREBP-1c expression. Activation of PKA repressed LXR-induced SREBP-1c expression
both in rat primary hepatocytes and mouse livers. Promoter analyses revealed that the LXRα-binding site in the SREBP-1c promoter
is responsible for PKA inhibitory effect on SREBP-1c transcription. In vitro and in vivo PKA directly phosphorylated LXRα, and the two consensus PKA target sites (195, 196 serines and 290, 291 serines) in its ligand
binding/heterodimerization domain were crucial for the inhibition of LXR signaling. PKA phosphorylation of LXRα caused impaired
DNA binding activity by preventing LXRα/RXR dimerization and decreased its transcription activity by inhibiting recruitment
of coactivator SCR-1 and enhancing recruitment of corepressor NcoR1. These results indicate that LXRα is regulated not only
by oxysterol derivatives but also by PKA-mediated phosphorylation, which suggests that nutritional regulation of SREBP-1c
and lipogenesis could be regulated at least partially through modulation of LXR.
Full-text · Article · May 2007 · Journal of Biological Chemistry
[Show abstract][Hide abstract] ABSTRACT: Granuphilin is a crucial component of the docking machinery of insulin-containing vesicles to the plasma membrane. Here, we show that the granuphilin promoter is a target of SREBP-1c, a transcription factor that controls fatty acid synthesis, and MafA, a beta cell differentiation factor. Potassium-stimulated insulin secretion (KSIS) was suppressed in islets with adenoviral-mediated overexpression of granuphilin and enhanced in islets with knockdown of granuphilin (in which granuphilin had been knocked down). SREBP-1c and granuphilin were activated in islets from beta cell-specific SREBP-1c transgenic mice, as well as in several diabetic mouse models and normal islets treated with palmitate, accompanied by a corresponding reduction in insulin secretion. Knockdown- or knockout-mediated ablation of granuphilin or SREBP-1c restored KSIS in these islets. Collectively, our data provide evidence that activation of the SREBP-1c/granuphilin pathway is a potential mechanism for impaired insulin secretion in diabetes, contributing to beta cell lipotoxicity.
[Show abstract][Hide abstract] ABSTRACT: The centrosome plays a fundamental role in cell division, cell polarity, and cell cycle progression. Centrosome duplication is mainly controlled by cyclin-dependent kinase 2 (CDK2)/cyclin E and cyclin A complexes, which are inhibited by the CDK inhibitors p21Cip1 and p27Kip1. It is thought that abnormal activation of CDK2 induces centrosome amplification that is frequently observed in a wide range of aggressive tumors. We previously reported that overexpression of the oncogene MYCN leads to centrosome amplification after DNA damage in neuroblastoma cells. We here show that centrosome amplification after gamma-irradiation was caused by suppression of p27 expression in MYCN-overexpressing cells. We further show that p27-/- and p27+/- mouse embryonic fibroblasts and p27-silenced human cells exhibited a significant increase in centrosome amplification after DNA damage. Moreover, abnormal mitotic cells with amplified centrosomes were frequently observed in p27-silenced cells. In response to DNA damage, the level of p27 gradually increased in normal cells independently of the ataxia telangiectasia mutated/p53 pathway, whereas Skp2, an F-box protein component of an SCF ubiquitin ligase complex that targets p27, was reduced. Additionally, p27 levels in MYCN-overexpressing cells were restored by treatment with Skp2 small interfering RNA, indicating that down-regulation of p27 by MYCN was due to high expression of Skp2. These results suggest that the accumulation of p27 after DNA damage is required for suppression of centrosome amplification, thereby preventing chromosomal instability.
[Show abstract][Hide abstract] ABSTRACT: Using an expression cloning strategy, we have identified TFE3, a basic helix-loop-helix protein, as a transactivator of metabolic genes that are regulated through an E-box in their promoters. Adenovirus-mediated expression of TFE3 in hepatocytes in culture and in vivo strongly activated expression of IRS-2 and Akt and enhanced phosphorylation of insulin-signaling kinases such as Akt, glycogen synthase kinase 3beta and p70S6 kinase. TFE3 also induced hexokinase II (HK2) and insulin-induced gene 1 (INSIG1). These changes led to metabolic consequences, such as activation of glycogen and protein synthesis, but not lipogenesis, in liver. Collectively, plasma glucose levels were markedly reduced both in normal mice and in different mouse models of diabetes, including streptozotocin-treated, db/db and KK mice. Promoter analyses showed that IRS2, HK2 and INSIG1 are direct targets of TFE3. Activation of insulin signals in both insulin depletion and resistance suggests that TFE3 could be a therapeutic target for diabetes.
[Show abstract][Hide abstract] ABSTRACT: Pericyte ghosts and acellular capillaries are well known as early histological changes resulting from diabetic retinopathy. These histological changes mean that the cell death of retinal microvessels has accelerated. It was reported that apoptosis of retinal microvascular cells (RMCs) was increased in diabetic patients. Therefore, we investigated apoptosis of RMCs in Goto-Kakizaki (GK) rats, a type 2 diabetic model, and involvement with antioxidants (a combination of vitamins C and E) or a novel inhibitor of advanced glycation, OPB-9195.
GK rats were treated with the antioxidants combination or OPB-9195 for 36 weeks. We obtained isolated preparations of the vascular network from their retinas by trypsin digestion. Apoptosis of retinal vascular cells was detected with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay.
We found that apoptosis of RMCs was increased in the diabetic GK rats. Furthermore, a combination of vitamins C and E and an advanced glycation end-products inhibitor mostly inhibited this increased apoptosis.
We concluded that apoptosis of RMCs was a good marker that indicates the progression of diabetic retinopathy in GK rats. Both oxidative stress and the accumulation of advanced glycation end-products appears to promote the apoptosis of retinal microvascular cells, and antioxidants or advanced glycation end-products inhibitors might ameliorate diabetic retinopathy.
Full-text · Article · Jan 2006 · Diabetes/Metabolism Research and Reviews
[Show abstract][Hide abstract] ABSTRACT: Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that regulate lipid synthetic
genes. In contrast to SREBP-2, which regulates cellular cholesterol level in normal cells, SREBP-1a is highly expressed in
actively growing cells and activates entire programs of genes involved in lipid synthesis such as cholesterol, fatty acids,
triglycerides, and phospholipids. Previously, the physiological relevance of this potent activity of SREBP-1a has been thought
to regulate the supply of membrane lipids in response to cell growth. Here we show that nuclear SREBP-1a and SREBP-2 bind
directly to a novel SREBP binding site in the promoter of the p21WAF1/CIP1 gene, the major cyclin-dependent kinase inhibitor, and strongly activate its promoter activity. Only the SREBP-1a isoform
consistently causes induction of p21 at both the mRNA and protein levels. Colony formation assays and polyploidy of livers
from transgenic mice suggest that activation of p21 by SREBP-1a could inhibit cell growth. Activation of endogenous SREBPs
in lipid deprivation conditions was associated with induction of p21 mRNA and protein. Expression of p21 was reduced in SREBP-1
null mice. These data suggest a physiological role of SREBP-1a in p21 regulation. Identification of p21 as a new SREBP target
might implicate a new paradigm in the link between lipid synthesis and cell growth.
Full-text · Article · Nov 2005 · Molecular and Cellular Biology
[Show abstract][Hide abstract] ABSTRACT: Sterol regulatory element-binding protein-1 (SREBP-1) is a transcription factor which regulates genes involved in the synthesis of fatty acids and triglycerides. The overexpression of nuclear SREBP-1a in transgenic mice under the control of the PEPCK promoter (TgSREBP-1a) caused a massively enlarged fatty liver and disappearance of peripheral white adipose tissue. In the current study, we estimated the impact of this lipid transcription factor on plasma glucose/insulin metabolism in vivo. TgSREBP-1a exhibited mild peripheral insulin resistance as evidenced by hyperinsulinemia both at fasting and after intravenous glucose loading, and retarded glucose reduction after insulin injection due to decreased plasma leptin levels. Intriguingly, hyperinsulinemia in TgSREBP-1a mice was markedly exacerbated in a fed state and sustained after intravenous glucose loading, and paradoxically decreased after the portal injection of glucose. TgSREBP-1a mice consistently showed very small plasma glucose increases after portal glucose loading because of a large capacity for hepatic glucose uptake. These data suggested that hepatic insulin resistance emerges postprandially. In addition, pancreatic islets from TgSREBP-1a were enlarged. These data demonstrate that SREBP-1a activation in the liver has a strong impact on plasma insulin levels, implicating the potential role of SREBPs in hepatic insulin metabolism relating to insulin resistance.