For a long time it has been known that obesity (adiposity) is linked to insulin resistance. Recently, many investigators have reported that adipocytes secrete a variety of bioactive molecules, termed adipokines (adipocytokines), including TNFalpha, IL-6, leptin, adiponectin, resistin and so on. These adipokines play pivotal roles in energy homeostasis by affecting insulin sensitivity, glucose and lipid metabolisms, food intake, the coagulation system and inflammation. This review provides a summary of these adipose tissue-secreting biomolecules and discusses their feasibilities as drug targets for the treatment of metabolic syndrome.
Mutations in the NR0B1 gene, also well-known as the DAX1 gene, are known to cause congenital adrenal hypoplasia associated with hypogonadotropic hypogonadism. The abnormal NR0B1 protein fails to suppress the transcription of promoters of steroidogenic enzymes, which are also targets of NR5A1 protein, also well-known as Ad4BP/SF-1 protein. Since NR5A1 and NR0B1 have antagonistic effects on steroidogenesis, the loss of function due to NR0B1 mutations may be compensated by inducing loss of function of NR5A1 protein.A middle-aged man was diagnosed with congenital adrenal hypoplasia associated with hypogonadotropic hypogonadism and genetic analysis revealed him to have a novel NR0B1 mutation, c.1222C>T(p.Gln408Ter).NR0B1 activity was evaluated in CLK1/4 inhibitor-treated 293T cells via immunoblotting and luciferase assays of the STAR promoter.TG003 treatment suppressed NR5A1 protein function to compensate for the mutant NR0B1 showing inhibited suppression of transcription. Immunoblotting analyses showed that the phosphorylation status of NR5A1 at Ser203 was attenuated by the CLK1/4 inhibitor.The specific reduction of NR5A1 phosphorylation by a CLK1/4 inhibitor may alleviate developmental defects in patients with NR0B1 mutations.
The intracellular concentration of the microsomal triglyceride transfer protein large subunit (lMTP), the abetalipoproteinemia gene product, is tightly controlled. To date, attempts at overexpressing lMTP in vivo or in vitro have been unsuccessful. We successfully overexpressed lMTP in HepG2 cells using an adenoviral vector containing an lMTP cDNA, AdMTP. AdMTP-transduced HepG2 cells overexpressed MTP activity. They secreted increased amounts of apoB-100 lipoproteins with LDL and HDL density into the medium. lMTP overexpression alone minimally changed the density profile of apoB-containing lipoproteins, but addition of oleic acid shifted the profile toward lower densities. Oleic acid had a greater stimulatory effect on apoB-100 secretion in control HepG2 cells than in AdMTP-transduced cells, because (i) adenoviral transduction per se suppressed protein synthesis, affecting apoB-100 and albumin equally, and (ii) adenoviral transduction partially attenuated the increase in triglyceride synthesis in response to oleic acid supplementation. AdMTP treatment greatly diminished the intracellular degradation of apoB-100, but in comparison with recombinant virus containing luciferase cDNA (AdLuc), it caused no change in its biosynthetic rate. It greatly reduced, but did not eliminate, its proteasomal degradation. Our study constitutes the initial demonstration that adenovirus-mediated transfer of lMTP markedly stimulates MTP expression which in turn stimulates apoB-100 production. The mechanism involves a downregulation of ubiquitin-proteasome-mediated degradation without any change in synthetic rate.
Abstract Purpose: In this retrospective study, we investigated the status and validity of endoscopic transsphenoidal surgery (eTSS) for pituitary incidentalomas (PIs) as well as the value of basing the indication for surgery on the PI guidelines. Methods: Patients who underwent eTSS at Fukuoka University Chikushi Hospital between 2012 and 2018 were divided into the PI group and the non-PI group in accordance with the PI guideline of the Endocrine Society and their clinicopathological characteristics and outcomes were compared and analyzed. Results: A total of 59 patients were enrolled, with 35 patients in the PI group and 24 patients in the non-PI group. The diagnoses in the PI group were of non-functioning pituitary adenoma (NFPA) (n = 12, 34%), gonadotropin-producing pituitary adenoma (n = 8, 23%), Rathke cleft cyst (n = 7, 20%), meningioma (n = 4, 11%), and growth hormone-producing pituitary adenoma (n = 3, 9%); those in the non-PI group were of NFPA (n = 6, 25%), gonadotropin-producing pituitary adenoma (n = 3, 13%), Rathke cleft cyst (n = 3, 13%), growth hormone-producing pituitary adenoma (n = 3, 13%), and prolactin producing pituitary adenoma (n = 3, 13%). Regarding the preoperative factors, 1 patient in the PI group with panhypopituitarism was diagnosed with pituitary apoplexy (pure infarction) of an NFPA. The rates of postoperative anterior pituitary hormonal deficiencies (14% vs 46%, P = .015), residual tumor size (2 ± 5 vs 6 ± 7 mm, P = .008), and reoperation (n = 0, 0% vs n = 5, 21%, P = .005) were significantly different between the PI and non-PI groups. Conclusions: This study showed that, postoperatively, the incidence of anterior pituitary hormonal deficiencies was lower in the PI than in the non-PI group, although it was comparable between the 2 groups before the operation. The patients in the PI group also had smaller residual tumors and a lower risk of reoperation than those in non-PI group. PIs could have a better postoperative clinical outcome than non-PIs when the indication for eTSS is based on preoperative scrutiny according to the PI guidelines and eTSS is performed by an experienced pituitary surgeon. Hence, more aggressive scrutiny and treatment for PIs might be desirable.
The interaction of lipoprotein lipase (LPL) with triglyceride-rich lipoproteins is governed by a number of factors, such as apolipoprotein (apo) C-II. The role of apoE in lipolysis is controversial. We made the unexpected observation that apoE-deficient mice were resistant to heparin-induced lipolysis; this study aims at examining the underlying mechanism for this observation. Compared to wild-type mice, apoE-deficient mice had significantly higher very low density lipoprotein (VLDL) and chylomicron remnant (VLDL/CMR) concentrations and moderately lower lipase activity (15.5 ± 1.3 mU/ml vs. 22.9 ± 2.5 mU/ml). Unlike in wild-type mice where the injection of heparin reduced total plasma triglycerides by 50% and VLDL/CMR triglycerides by over 95%, the injection of heparin into apoE-deficient mice did not significantly affect plasma lipids. Similarly, in vitro, purified human LPL (hLPL) almost completely hydrolyzed VLDL/CMR isolated from wild-type mice, but had no effect on VLDL/CMR from apoE-deficient mice. However, when the amount of apoE-deficient VLDL/CMR was reduced to an equivalent level as in wild-type mice, LPL hydrolyzed 94% of VLDL/CMR triglycerides. In order to increase the ratio of LPL to VLDL/CMR in vivo, we injected an adenovirus containing the human LPL cDNA into apoE-deficient mice, which produced marked liver-specific overexpression of LPL and significant reduction of VLDL/CMR (93%) and total plasma triglyceride concentrations (87%). Thus, apoE is not required for LPL activity in vivo or in vitro. Under certain pathological conditions, such as severe hyperlipidemia, the LPL pathway may be saturated and efficient lipolysis can proceed only if the ratio of substrate particles to LPL is adjusted to a more normal range.—Zsigmond, E., Y. Fuke, L. Li, K. Kobayashi, and L. Chan. Resistance of chylomicron and VLDL remnants to post-heparin lipolysis in apoE-deficient mice: the role of apoE in lipoprotein lipase-mediated lipolysis in vivo and in vitro. J. Lipid Res.
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