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1 Protection Against Insulin Resistance by Apolipoprotein M/Sphingosine 1-Phosphate Makoto Kurano,1 Kazuhisa Tsukamoto,2, 3 Tomo

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1 Protection Against Insulin Resistance by Apolipoprotein M/Sphingosine 1-Phosphate Makoto Kurano,1 Kazuhisa Tsukamoto,2, 3 Tomo Page 1 of 67 Diabetes Protection against insulin resistance by apolipoprotein M/sphingosine 1-phosphate Makoto Kurano,1 Kazuhisa Tsukamoto,2, 3 Tomo Shimizu,4 Hidetoshi Kassai,5 Kazuki Nakao,5 Atsu Aiba,5 Masumi Hara,6 and Yutaka Yatomi,1 1Department of Clinical Laboratory Medicine and 5Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; 2Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan; 3Department of Metabolism, Diabetes and Nephrology, Aizu Medical Center, Fukushima Medical University, Fukushima, Japan; 4Tsukuba Research Institute, Research & Development Division, Sekisui Medical Co., Ltd., Ibaraki, Japan; 6Department of Internal Medicine, Mizonokuchi Hospital, Teikyo University School of Medicine, Kanagawa, Japan. Running Title: Apolipoprotein M and insulin resistance Address correspondence to: Makoto Kurano, MD, PhD and Yutaka Yatomi, MD, PhD. Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Tel: +81-3-3815-5411; 1 Diabetes Publish Ahead of Print, published online January 8, 2020 Diabetes Page 2 of 67 Fax: +81-3-5689-0495; E-mail: [email protected] (M.K.), [email protected] (Y.Y.) 2 Page 3 of 67 Diabetes List of Abbreviations: ApoM, apolipoprotein M; CM-ApoM, conditioned medium of apoM-overexpressing HepG2 cells; CM-GFP, conditioned medium of GFP-overexpressing HepG2 cells; CM-Null, conditioned medium of HepG2 infected with blank adenovirus; EP, epididymal; HFD, high fat diet; huApoM mice, mice injected with an adenovirus vector encoding human apoM; ITT, insulin tolerance test; JTE, JTE013; KO, knockout; LDLr, LDL receptor; siCtl, control siRNA; siApoM, siRNA against ApoM; siSIRT1, siRNA against SIRT1; S1P, sphingosine 1-phosphate; S1P1, S1P receptor 1; S1P2, S1P receptor 2; S1P3, S1P receptor 3; VPC, VPC23019; WT, wild type 3 Diabetes Page 4 of 67 Abstract Subjects with low serum HDL-cholesterol levels are reported to be susceptible to diabetes mellitus, with insulin resistance believed to be the underlying pathological mechanism. Apolipoprotein M (ApoM) is a carrier of sphingosine 1-phosphate (S1P), a multifunctional lipid mediator, on HDL, and the pleiotropic effects of HDL are believed to be mediated by S1P. In the present study, we attempted to investigate the potential association between apoM/S1P and insulin resistance. We observed that the serum levels of apoM were lower in patients with type 2 diabetes mellitus and that they were negatively correlated with the BMI and the insulin resistance index. While deletion of apoM in mice was associated with worsening of insulin resistance, overexpression of apoM was associated with improvement of insulin resistance. Presumably, apoM/S1P exerts its protective effect against insulin resistance by activating insulin signaling pathways, such as the AKT and AMPK pathways, and also improving the mitochondrial functions through upregulating the SIRT1 protein levels. These actions of apoM/S1P appear to be mediated via activation of S1P1 and/or S1P3. These results suggest that ApoM/S1P exerts protective roles against the development of insulin resistance. Keywords: apolipoprotein M, sphingosine 1-phosphate, insulin resistance, mitochondria, SIRT1 4 Page 5 of 67 Diabetes Introduction Insulin resistance is one of the main pathogenetic mechanisms of type 2 diabetes mellitus. Subjects with insulin resistance often exhibit low serum levels of HDL-cholesterol, which could explain, in part, the pro-atherosclerotic effect of insulin resistance (1). In addition, subjects with low serum HDL-cholesterol levels are also reportedly susceptible to the development of diabetes mellitus (2-4). Although the anti-inflammatory actions (5) or its roles in the reverse cholesterol transfer system (6) of HDL might partly explain these epidemiological associations, the precise mechanisms have yet to be elucidated. Sphingosine 1-phosphate (S1P) is carried on apolipoprotein M (apoM) (7), a minor apolipoprotein on HDL (8), and has been proposed as being responsible for many of the pleiotropic effects of HDL, such as anti-apoptotic (9), anti-inflammatory (10), and vasoprotective effects (11). In regard to the clinical association between apoM and diabetes mellitus, SNPs of apoM have been shown to be associated with type 1 and type 2 diabetes mellitus (12; 13) and serum apoM levels have been demonstrated to be lower in subjects with MODY3 diabetes (14). As for the mechanisms underlying the association between apoM/S1P and diabetes mellitus, we have reported that apoM promotes insulin secretion through activation of S1P receptor 1 (S1P1) and/or S1P receptor 3 (S1P3) signaling (15). One recent study reported that apoM suppresses the activity of brown adipose tissue and that deficiency of apoM protects mice against diet-induced obesity and also, to some extent, against glucose intolerance (16). However, the association between apoM/S1P and insulin resistance has not yet been clearly elucidated, especially in terms of the disturbed glucose metabolism in the liver and skeletal muscles, which is involved in the pathogenesis of insulin resistance, as well as in the adipose tissue. 5 Diabetes Page 6 of 67 In the present study, considering these background data, we hypothesized that apoM/S1P might explain the protective effects of HDL against the development of diabetes mellitus and investigated the roles of apoM/S1P in protecting against the glucose intolerance, especially insulin resistance. Research Design and Methods Materials and reagents The commercially available materials and reagents used in the present study are listed in Table S1–4 and were used according to the manufacturers’ protocols. Human subjects We collected serum samples from subjects who had fasted overnight prior to undergoing a medical examination at the Aizu Fujitsu Semiconductor Ltd. (n = 179), and from outpatients with type 2 diabetes mellitus who had fasted overnight (n = 46), at the Aizu Medical Center, Fukushima Medical University, after applying the following exclusion criteria: persons receiving insulin therapy, persons receiving anti-dyslipidemia reagents, and persons with severe renal complications (albuminuria >300 mg/g Cre or eGFR <30 mL/min/1.73 m2) (17). The clinical characteristics of the subjects are shown in Table 1. The present study was conducted with the approval of the Institutional Research Ethics Committee of Fukushima Medical University and Aizu Fujitsu Semiconductor Ltd., and written informed consent was obtained from each of the subjects (2041, UMIN000015010). Animal Experiments For investigating the modulation of apoM and S1P by insulin resistance, wild-type (WT) C57BL6 mice obtained from CLEA, Japan (Tokyo, Japan) were fed chow, a 60% HFD 6 Page 7 of 67 Diabetes (HFD-60; Oriental Yeast Co. Ltd., Tokyo, Japan), a choline methionine-deficient diet (F2MCD; Oriental Yeast Co. Ltd.), or a 60% HF supplemented with 1% cholesterol (HF + HC, n = 6) for 12 weeks from 8 weeks old. For the experiments with ApoM-KO mice, ApoM-KO mice were generated using the CRISPR-Cas9 system, as described previously (18). ApoM-KO mice and WT mice, their littermates, were fed chow or a HFD from 8 weeks old for 12 weeks or 18 months. For investigating the effects of apoM overexpression, 20-week-old WT mice reared on a HFD for 12 weeks were injected with an adenovirus vector encoding human apoM (huApoM mice) or a control blank adenovirus vector (WT mice) via the tail vein, at a dose of 2.5 X 108 pfu/g BW (19). To investigate the effects of VPC23019 (VPC), an antagonist against S1P1/3, or JTE013 (JTE), an antagonist against S1P2, the mice were intraperitoneally injected with vehicle alone, VPC (0.75 mg/kg BW) or JTE (0.75 mg/kg BW) twice a day from the second day after administration of the viral vector until 1 hour before the mice were sacrificed. We used VPC and JTE, as they are commonly used antagonists for the S1P receptors. We performed a glucose tolerance tests and an insulin tolerance test (ITT) as follows; the mice were denied access to food for 6 hours and challenged intraperitoneally with glucose (2 g/kg body weight) or Humulin R (0.5 U/kg or 0.375 U/kg body weight). All the animal experiments were conducted in accordance with the guidelines for Animal Care and were approved by the animal committee of The University of Tokyo (P11- 074, P16-044) Measurements of S1P, blood glucose, and hepatic lipids, metabolome analyses, and ELISA analyses 7 Diabetes Page 8 of 67 The plasma S1P levels were measured by a previously validated high-performance liquid chromatography method, as described in previous papers (20). Hepatic lipid was extracted with methanol and chloroform, and the cholesterol and triglyceride levels were measured by enzymatic methods and adjusted with the hepatic protein levels. Blood glucose was measured using a Glutest sensor. Metabolome analyses were performed with a gas chromatography mass spectrometry system (QP2020; SHIMAZU) as described previously (21). The ELISA kits utilized in the present study are listed in Table S1. The human apoM levels were measured by an ELISA method developed and validated by us, as described previously (15). Cell Experiments HepG2 cells (American Type Culture Collection, Manassas, VA), 3T3L1 fibroblasts (JCRB cell bank, Japan), and C2C12 myocytes (ECACC, UK) were cultured in DMEM supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin. The 3T3L1 fibroblasts and C2C12 cells were used after induction of adipogenic and myogenic differentiation with 0.5 mM 3-isobutyl-1-methylxanthine, 1 µM dexamethasone and 10 µg/mL of insulin, and 2% horse serum, respectively. To investigate the effects of overexpression or knockdown of apoM, HepG2 cells were infected with an adenovirus vector encoding apoM or GFP at a multiplicity of infection of 25, or treated with siRNA against apoM or control siRNA, using lipofectamine RNAi MAX. After 48 hours, the medium was replaced with FBS-free medium, and then 24 hours later, the cellular contents were collected and subjected to the analyses.
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