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Kubo H, Imai J, Izumi T, Kohata M, Kawana Y, Endo A, Sugawara H, Seike J, Horiuchi T, Komamura H, Sato T, Hosaka S, Asai Y, Kodama S, Takahashi K, Kaneko K, Katagiri H. Colonic inflammation triggers β cell proliferation during obesity development via a liver-to-pancreas interorgan mechanism. JCI Insight 2025; 10:e183864. [PMID: 40337860 DOI: 10.1172/jci.insight.183864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 03/21/2025] [Indexed: 05/09/2025] Open
Abstract
Under insulin-resistant conditions, such as obesity, pancreatic β cells adaptively proliferate and secrete more insulin to prevent blood glucose elevation. We previously reported hepatic ERK activation during obesity development to stimulate a neuronal relay system, consisting of afferent splanchnic nerves from the liver and efferent vagal nerves to the pancreas, thereby triggering adaptive β cell proliferation. However, the mechanism linking obesity with the interorgan system originating in hepatic ERK activation remains unclear. Herein, we clarified that colonic inflammation promotes β cell proliferation through this interorgan system from the liver to the pancreas. First, dextran sodium sulfate (DSS) treatment induced colonic inflammation and hepatic ERK activation as well as β cell proliferation, all of which were suppressed by blockades of the neuronal relay system by several approaches. In addition, treatment with anti-lymphocyte Peyer's patch adhesion molecule-1 (anti-LPAM1) antibody suppressed β cell proliferation induced by DSS treatment. Importantly, high-fat diet (HFD) feeding also elicited colonic inflammation, and its inhibition by anti-LPAM1 antibody administration suppressed hepatic ERK activation and β cell proliferation induced by HFD. Thus, colonic inflammation triggers adaptive β cell proliferation via the interorgan mechanism originating in hepatic ERK activation. The present study revealed a potentially novel role of the gastrointestinal tract in the maintenance of β cell regulation.
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Uno K, Uchino T, Suzuki T, Sayama Y, Edo N, Uno-Eder K, Morita K, Ishikawa T, Koizumi M, Honda H, Katagiri H, Tsukamoto K. Rspo3-mediated metabolic liver zonation regulates systemic glucose metabolism and body mass in mice. PLoS Biol 2025; 23:e3002955. [PMID: 39854351 PMCID: PMC11759367 DOI: 10.1371/journal.pbio.3002955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 11/27/2024] [Indexed: 01/26/2025] Open
Abstract
The unique architecture of the liver consists of hepatic lobules, dividing the hepatic features of metabolism into 2 distinct zones, namely the pericentral and periportal zones, the spatial characteristics of which are broadly defined as metabolic zonation. R-spondin3 (Rspo3), a bioactive protein promoting the Wnt signaling pathway, regulates metabolic features especially around hepatic central veins. However, the functional impact of hepatic metabolic zonation, regulated by the Rspo3/Wnt signaling pathway, on whole-body metabolism homeostasis remains poorly understood. In this study, we analyze the local functions of Rspo3 in the liver and the remote actions of hepatic Rspo3 on other organs of the body by using murine models. Rspo3 expression analysis shows that Rspo3 expression patterns are spatiotemporally controlled in the murine liver such that it locates in the pericentral zones and converges after feeding, and the dynamics of these processes are disturbed in obesity. We find that viral-mediated induction of Rspo3 in hepatic tissue of obesity improves insulin resistance and prevents body weight gain by restoring attenuated organ insulin sensitivities, reducing adipose tissue enlargement and reversing overstimulated adaptive thermogenesis. Denervation of the hepatic vagus suppresses these remote effects, derived from hepatic Rspo3 induction, toward adipose tissues and skeletal muscle, suggesting that signals are transduced via the neuronal communication consisting of afferent vagal and efferent sympathetic nerves. Furthermore, the non-neuronal inter-organ communication up-regulating muscle lipid utilization is partially responsible for the ameliorations of both fatty liver development and reduced skeletal muscle quality in obesity. In contrast, hepatic Rspo3 suppression through Cre-LoxP-mediated recombination system exacerbates diabetes due to glucose intolerance and insulin resistance, promotes fatty liver development and decreases skeletal muscle quality, resulting in obesity. Taken together, our study results reveal that modulation of hepatic Rspo3 contributes to maintaining systemic glucose metabolism and body composition via a newly identified inter-organ communication mechanism.
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Affiliation(s)
- Kenji Uno
- Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Takuya Uchino
- Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Takashi Suzuki
- Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Yohei Sayama
- Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Naoki Edo
- Teikyo Academic Research Center, Tokyo, Japan
| | | | - Koji Morita
- Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Toshio Ishikawa
- Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Miho Koizumi
- Field of Human Disease Models, Tokyo Women’s Medical University, Tokyo, Japan
| | - Hiroaki Honda
- Field of Human Disease Models, Tokyo Women’s Medical University, Tokyo, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazuhisa Tsukamoto
- Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
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Izumi M, Nakanishi Y, Kang S, Kumanogoh A. Peripheral and central regulation of neuro-immune crosstalk. Inflamm Regen 2024; 44:41. [PMID: 39327628 PMCID: PMC11426056 DOI: 10.1186/s41232-024-00352-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 09/12/2024] [Indexed: 09/28/2024] Open
Abstract
The neural and immune systems sense and respond to external stimuli to maintain tissue homeostasis. These systems do not function independently but rather interact with each other to effectively exert biological actions and prevent disease pathogenesis, such as metabolic, inflammatory, and infectious disorders. Mutual communication between these systems is also affected by tissue niche-specific signals that reflect the tissue environment. However, the regulatory mechanisms underlying these interactions are not completely understood. In addition to the peripheral regulation of neuro-immune crosstalk, recent studies have reported that the central nervous system plays essential roles in the regulation of systemic neuro-immune interactions. In this review, we provide an overview of the molecular basis of peripheral and systemic neuro-immune crosstalk and explore how these multilayered interactions are maintained.
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Affiliation(s)
- Mayuko Izumi
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
- Department of Immunopathology, World Premier International Research Center Initiative Immunology Frontier Research Center (WPI-IFReC), Osaka University, Osaka, 565-0871, Japan
- Department of Advanced Clinical and Translational Immunology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, 565-0871, Japan
| | - Yoshimitsu Nakanishi
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
- Department of Immunopathology, World Premier International Research Center Initiative Immunology Frontier Research Center (WPI-IFReC), Osaka University, Osaka, 565-0871, Japan
- Department of Advanced Clinical and Translational Immunology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, 565-0871, Japan
| | - Sujin Kang
- Laboratory of Immune Regulation, WPI-IFReC, Osaka University, Osaka, 565-0871, Japan
- Center for Infectious Diseases for Education and Research (CiDER), Osaka University, Osaka, 565-0871, Japan
| | - Atsushi Kumanogoh
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan.
- Department of Immunopathology, World Premier International Research Center Initiative Immunology Frontier Research Center (WPI-IFReC), Osaka University, Osaka, 565-0871, Japan.
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, 565-0871, Japan.
- Center for Infectious Diseases for Education and Research (CiDER), Osaka University, Osaka, 565-0871, Japan.
- Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Osaka University, Osaka, 565-0871, Japan.
- Center for Advanced Modalities and DDS (CAMaD), Osaka University, Osaka, 565-0871, Japan.
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Nishida K, Ueno S, Seino Y, Hidaka S, Murao N, Asano Y, Fujisawa H, Shibata M, Takayanagi T, Ohbayashi K, Iwasaki Y, Iizuka K, Okuda S, Tanaka M, Fujii T, Tochio T, Yabe D, Yamada Y, Sugimura Y, Hirooka Y, Hayashi Y, Suzuki A. Impaired Fat Absorption from Intestinal Tract in High-Fat Diet Fed Male Mice Deficient in Proglucagon-Derived Peptides. Nutrients 2024; 16:2270. [PMID: 39064713 PMCID: PMC11280123 DOI: 10.3390/nu16142270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 07/10/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
(1) Background: Proglucagon-derived peptides (PDGPs) including glucagon (Gcg), GLP-1, and GLP-2 regulate lipid metabolism in the liver, adipocytes, and intestine. However, the mechanism by which PGDPs participate in alterations in lipid metabolism induced by high-fat diet (HFD) feeding has not been elucidated. (2) Methods: Mice deficient in PGDP (GCGKO) and control mice were fed HFD for 7 days and analyzed, and differences in lipid metabolism in the liver, adipose tissue, and duodenum were investigated. (3) Results: GCGKO mice under HFD showed lower expression levels of the genes involved in free fatty acid (FFA) oxidation such as Hsl, Atgl, Cpt1a, Acox1 (p < 0.05), and Pparα (p = 0.05) mRNA in the liver than in control mice, and both FFA and triglycerides content in liver and adipose tissue weight were lower in the GCGKO mice. On the other hand, phosphorylation of hormone-sensitive lipase (HSL) in white adipose tissue did not differ between the two groups. GCGKO mice under HFD exhibited lower expression levels of Pparα and Cd36 mRNA in the duodenum as well as increased fecal cholesterol contents compared to HFD-controls. (4) Conclusions: GCGKO mice fed HFD exhibit a lesser increase in hepatic FFA and triglyceride contents and adipose tissue weight, despite reduced β-oxidation in the liver, than in control mice. Thus, the absence of PGDP prevents dietary-induced fatty liver development due to decreased lipid uptake in the intestinal tract.
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Affiliation(s)
- Koki Nishida
- Departments of Endocrinology, Diabetes and Metabolism, Fujita Health University School of Medicine, Toyoake 470-1192, Japan; (K.N.); (S.U.); (S.H.); (N.M.); (Y.A.); (H.F.); (M.S.); (T.T.); (Y.S.); (A.S.)
| | - Shinji Ueno
- Departments of Endocrinology, Diabetes and Metabolism, Fujita Health University School of Medicine, Toyoake 470-1192, Japan; (K.N.); (S.U.); (S.H.); (N.M.); (Y.A.); (H.F.); (M.S.); (T.T.); (Y.S.); (A.S.)
| | - Yusuke Seino
- Departments of Endocrinology, Diabetes and Metabolism, Fujita Health University School of Medicine, Toyoake 470-1192, Japan; (K.N.); (S.U.); (S.H.); (N.M.); (Y.A.); (H.F.); (M.S.); (T.T.); (Y.S.); (A.S.)
- Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kyoto 604-8436, Japan; (D.Y.); (Y.Y.)
| | - Shihomi Hidaka
- Departments of Endocrinology, Diabetes and Metabolism, Fujita Health University School of Medicine, Toyoake 470-1192, Japan; (K.N.); (S.U.); (S.H.); (N.M.); (Y.A.); (H.F.); (M.S.); (T.T.); (Y.S.); (A.S.)
| | - Naoya Murao
- Departments of Endocrinology, Diabetes and Metabolism, Fujita Health University School of Medicine, Toyoake 470-1192, Japan; (K.N.); (S.U.); (S.H.); (N.M.); (Y.A.); (H.F.); (M.S.); (T.T.); (Y.S.); (A.S.)
- Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kyoto 604-8436, Japan; (D.Y.); (Y.Y.)
| | - Yuki Asano
- Departments of Endocrinology, Diabetes and Metabolism, Fujita Health University School of Medicine, Toyoake 470-1192, Japan; (K.N.); (S.U.); (S.H.); (N.M.); (Y.A.); (H.F.); (M.S.); (T.T.); (Y.S.); (A.S.)
| | - Haruki Fujisawa
- Departments of Endocrinology, Diabetes and Metabolism, Fujita Health University School of Medicine, Toyoake 470-1192, Japan; (K.N.); (S.U.); (S.H.); (N.M.); (Y.A.); (H.F.); (M.S.); (T.T.); (Y.S.); (A.S.)
| | - Megumi Shibata
- Departments of Endocrinology, Diabetes and Metabolism, Fujita Health University School of Medicine, Toyoake 470-1192, Japan; (K.N.); (S.U.); (S.H.); (N.M.); (Y.A.); (H.F.); (M.S.); (T.T.); (Y.S.); (A.S.)
| | - Takeshi Takayanagi
- Departments of Endocrinology, Diabetes and Metabolism, Fujita Health University School of Medicine, Toyoake 470-1192, Japan; (K.N.); (S.U.); (S.H.); (N.M.); (Y.A.); (H.F.); (M.S.); (T.T.); (Y.S.); (A.S.)
| | - Kento Ohbayashi
- Laboratory of Animal Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan; (K.O.); (Y.I.)
| | - Yusaku Iwasaki
- Laboratory of Animal Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan; (K.O.); (Y.I.)
| | - Katsumi Iizuka
- Department of Clinical Nutrition, Fujita Health University, Toyoake 470-1192, Japan;
| | - Shoei Okuda
- Graduate School of Bioscience and Biotechnology, College of Bioscience and Biotechnology, Chubu University, Kasugai 487-8501, Japan; (S.O.); (M.T.)
| | - Mamoru Tanaka
- Graduate School of Bioscience and Biotechnology, College of Bioscience and Biotechnology, Chubu University, Kasugai 487-8501, Japan; (S.O.); (M.T.)
| | - Tadashi Fujii
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake 470-1192, Japan; (T.F.); (T.T.); (Y.H.)
- Department of Medical Research on Prebiotics and Probiotics, Fujita Health University, Toyoake 470-1101, Japan
- BIOSIS Lab. Co., Ltd., Toyoake 470-1192, Japan
| | - Takumi Tochio
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake 470-1192, Japan; (T.F.); (T.T.); (Y.H.)
- Department of Medical Research on Prebiotics and Probiotics, Fujita Health University, Toyoake 470-1101, Japan
- BIOSIS Lab. Co., Ltd., Toyoake 470-1192, Japan
| | - Daisuke Yabe
- Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kyoto 604-8436, Japan; (D.Y.); (Y.Y.)
- Center for One Medicine Innovative Translational Research, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Yuuichiro Yamada
- Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Kyoto 604-8436, Japan; (D.Y.); (Y.Y.)
| | - Yoshihisa Sugimura
- Departments of Endocrinology, Diabetes and Metabolism, Fujita Health University School of Medicine, Toyoake 470-1192, Japan; (K.N.); (S.U.); (S.H.); (N.M.); (Y.A.); (H.F.); (M.S.); (T.T.); (Y.S.); (A.S.)
| | - Yoshiki Hirooka
- Department of Gastroenterology and Hepatology, Fujita Health University, Toyoake 470-1192, Japan; (T.F.); (T.T.); (Y.H.)
- Department of Medical Research on Prebiotics and Probiotics, Fujita Health University, Toyoake 470-1101, Japan
- BIOSIS Lab. Co., Ltd., Toyoake 470-1192, Japan
| | - Yoshitaka Hayashi
- Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya 464-8601, Japan;
- Department of Endocrinology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Atsushi Suzuki
- Departments of Endocrinology, Diabetes and Metabolism, Fujita Health University School of Medicine, Toyoake 470-1192, Japan; (K.N.); (S.U.); (S.H.); (N.M.); (Y.A.); (H.F.); (M.S.); (T.T.); (Y.S.); (A.S.)
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5
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Marafie SK, Al-Mulla F, Abubaker J. mTOR: Its Critical Role in Metabolic Diseases, Cancer, and the Aging Process. Int J Mol Sci 2024; 25:6141. [PMID: 38892329 PMCID: PMC11173325 DOI: 10.3390/ijms25116141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 05/26/2024] [Accepted: 05/29/2024] [Indexed: 06/21/2024] Open
Abstract
The mammalian target of rapamycin (mTOR) is a pivotal regulator, integrating diverse environmental signals to control fundamental cellular functions, such as protein synthesis, cell growth, survival, and apoptosis. Embedded in a complex network of signaling pathways, mTOR dysregulation is implicated in the onset and progression of a range of human diseases, including metabolic disorders such as diabetes and cardiovascular diseases, as well as various cancers. mTOR also has a notable role in aging. Given its extensive biological impact, mTOR signaling is a prime therapeutic target for addressing these complex conditions. The development of mTOR inhibitors has proven advantageous in numerous research domains. This review delves into the significance of mTOR signaling, highlighting the critical components of this intricate network that contribute to disease. Additionally, it addresses the latest findings on mTOR inhibitors and their clinical implications. The review also emphasizes the importance of developing more effective next-generation mTOR inhibitors with dual functions to efficiently target the mTOR pathways. A comprehensive understanding of mTOR signaling will enable the development of effective therapeutic strategies for managing diseases associated with mTOR dysregulation.
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Affiliation(s)
- Sulaiman K. Marafie
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait
| | - Fahd Al-Mulla
- Department of Translational Research, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait;
| | - Jehad Abubaker
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait
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Berthoud HR, Münzberg H, Morrison CD, Neuhuber WL. Hepatic interoception in health and disease. Auton Neurosci 2024; 253:103174. [PMID: 38579493 PMCID: PMC11129274 DOI: 10.1016/j.autneu.2024.103174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 03/14/2024] [Accepted: 03/28/2024] [Indexed: 04/07/2024]
Abstract
The liver is a large organ with crucial functions in metabolism and immune defense, as well as blood homeostasis and detoxification, and it is clearly in bidirectional communication with the brain and rest of the body via both neural and humoral pathways. A host of neural sensory mechanisms have been proposed, but in contrast to the gut-brain axis, details for both the exact site and molecular signaling steps of their peripheral transduction mechanisms are generally lacking. Similarly, knowledge about function-specific sensory and motor components of both vagal and spinal access pathways to the hepatic parenchyma is missing. Lack of progress largely owes to controversies regarding selectivity of vagal access pathways and extent of hepatocyte innervation. In contrast, there is considerable evidence for glucose sensors in the wall of the hepatic portal vein and their importance for glucose handling by the liver and the brain and the systemic response to hypoglycemia. As liver diseases are on the rise globally, and there are intriguing associations between liver diseases and mental illnesses, it will be important to further dissect and identify both neural and humoral pathways that mediate hepatocyte-specific signals to relevant brain areas. The question of whether and how sensations from the liver contribute to interoceptive self-awareness has not yet been explored.
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Affiliation(s)
- Hans-Rudolf Berthoud
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA.
| | - Heike Münzberg
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Christopher D Morrison
- Neurobiology of Nutrition & Metabolism Department, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, USA
| | - Winfried L Neuhuber
- Institute for Anatomy and Cell Biology, Friedrich-Alexander University, Erlangen, Germany.
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Wan JF, Chen Y, Yao TH, Wu YZ, Dai HZ. Impact of body mass index on adverse kidney events in diabetes mellitus patients: A systematic-review and meta-analysis. World J Clin Cases 2024; 12:538-550. [PMID: 38322463 PMCID: PMC10841950 DOI: 10.12998/wjcc.v12.i3.538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 12/10/2023] [Accepted: 12/28/2023] [Indexed: 01/18/2024] Open
Abstract
BACKGROUND The incidence of chronic kidney disease among patients with diabetes mellitus (DM) remains a global concern. Long-term obesity is known to possibly influence the development of type 2 diabetes mellitus. However, no previous meta-analysis has assessed the effects of body mass index (BMI) on adverse kidney events in patients with DM. AIM To determine the impact of BMI on adverse kidney events in patients with DM. METHODS A systematic literature search was performed on the PubMed, ISI Web of Science, Scopus, Ovid, Google Scholar, EMBASE, and BMJ databases. We included trials with the following characteristics: (1) Type of study: Prospective, retrospective, randomized, and non-randomized in design; (2) participants: Restricted to patients with DM aged ≥ 18 years; (3) intervention: No intervention; and (4) kidney adverse events: Onset of diabetic kidney disease [estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2 and/or microalbuminuria value of ≥ 30 mg/g Cr], serum creatinine increase of more than double the baseline or end-stage renal disease (eGFR < 15 mL/min/1.73 m2 or dialysis), or death. RESULTS Overall, 11 studies involving 801 patients with DM were included. High BMI (≥ 25 kg/m2) was significantly associated with higher blood pressure (BP) [systolic BP by 0.20, 95% confidence interval (CI): 0.15-0.25, P < 0.00001; diastolic BP by 0.21 mmHg, 95%CI: 0.04-0.37, P = 0.010], serum albumin, triglycerides [standard mean difference (SMD) = 0.35, 95%CI: 0.29-0.41, P < 0.00001], low-density lipoprotein (SMD = 0.12, 95%CI: 0.04-0.20, P = 0.030), and lower high-density lipoprotein (SMD = -0.36, 95%CI: -0.51 to -0.21, P < 0.00001) in patients with DM compared with those with low BMIs (< 25 kg/m2). Our analysis showed that high BMI was associated with a higher risk ratio of adverse kidney events than low BMI (RR: 1.22, 95%CI: 1.01-1.43, P = 0.036). CONCLUSION The present analysis suggested that high BMI was a risk factor for adverse kidney events in patients with DM.
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Affiliation(s)
- Jing-Fang Wan
- Department of Nephrology, Army Medical University, Chongqing 400042, China
| | - Yan Chen
- Department of Nephrology, Chongqing Western Hospital, Chongqing 400052, China
| | - Tian-Hua Yao
- Health Statistics, Army Medical University, Chongqing 400038, China
| | - Ya-Zhou Wu
- Health Statistics, Army Medical University, Chongqing 400038, China
| | - Huan-Zi Dai
- Department of Nephrology, Daping Hospital, Army Medical University, Chongqing 400042, China
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Katagiri H. Inter-organ communication involved in metabolic regulation at the whole-body level. Inflamm Regen 2023; 43:60. [PMID: 38087385 PMCID: PMC10714542 DOI: 10.1186/s41232-023-00306-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 10/29/2023] [Indexed: 10/16/2024] Open
Abstract
Metabolism in each organ of multi-organ organisms, including humans, is regulated in a coordinated manner to dynamically maintain whole-body homeostasis. Metabolic information exchange among organs/tissues, i.e., inter-organ communication, which is necessary for this purpose, has been a subject of ongoing research. In particular, it has become clear that metabolism of energy, glucose, lipids, and amino acids is dynamically regulated at the whole-body level mediated by the nervous system, including afferent, central, and efferent nerves. These findings imply that the central nervous system obtains metabolic information from peripheral organs at all times and sends signals selectively to peripheral organs/tissues to maintain metabolic homeostasis, and that the liver plays an important role in sensing and transmitting information on the metabolic status of the body. Furthermore, the utilization of these endogenous mechanisms is expected to lead to the development of novel preventive/curative therapies for metabolic diseases such as diabetes and obesity.(This is a summarized version of the subject matter presented at Symposium 7 presented at the 43rd Annual Meeting of the Japanese Society of Inflammation and Regeneration.).
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Affiliation(s)
- Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan.
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Miyazaki T. Calpain and Cardiometabolic Diseases. Int J Mol Sci 2023; 24:16782. [PMID: 38069105 PMCID: PMC10705917 DOI: 10.3390/ijms242316782] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 11/20/2023] [Accepted: 11/22/2023] [Indexed: 12/18/2023] Open
Abstract
Calpain is defined as a member of the superfamily of cysteine proteases possessing the CysPC motif within the gene. Calpain-1 and -2, which are categorized as conventional isozymes, execute limited proteolysis in a calcium-dependent fashion. Accordingly, the calpain system participates in physiological and pathological phenomena, including cell migration, apoptosis, and synaptic plasticity. Recent investigations have unveiled the contributions of both conventional and unconventional calpains to the pathogenesis of cardiometabolic disorders. In the context of atherosclerosis, overactivation of conventional calpain attenuates the barrier function of vascular endothelial cells and decreases the immunosuppressive effects attributed to lymphatic endothelial cells. In addition, calpain-6 induces aberrant mRNA splicing in macrophages, conferring atheroprone properties. In terms of diabetes, polymorphisms of the calpain-10 gene can modify insulin secretion and glucose disposal. Moreover, conventional calpain reportedly participates in amino acid production from vascular endothelial cells to induce alteration of amino acid composition in the liver microenvironment, thereby facilitating steatohepatitis. Such multifaceted functionality of calpain underscores its potential as a promising candidate for pharmaceutical targets for the treatment of cardiometabolic diseases. Consequently, the present review highlights the pivotal role of calpains in the complications of cardiometabolic diseases and embarks upon a characterization of calpains as molecular targets.
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Affiliation(s)
- Takuro Miyazaki
- Department of Biochemistry, Showa University School of Medicine, Tokyo 142-8555, Japan
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10
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Takahashi K, Yamada T, Hosaka S, Kaneko K, Asai Y, Munakata Y, Seike J, Horiuchi T, Kodama S, Izumi T, Sawada S, Hoshikawa K, Inoue J, Masamune A, Ueno Y, Imai J, Katagiri H. Inter-organ insulin-leptin signal crosstalk from the liver enhances survival during food shortages. Cell Rep 2023:112415. [PMID: 37116488 DOI: 10.1016/j.celrep.2023.112415] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 02/27/2023] [Accepted: 04/04/2023] [Indexed: 04/30/2023] Open
Abstract
Crosstalk among organs/tissues is important for regulating systemic metabolism. Here, we demonstrate inter-organ crosstalk between hepatic insulin and hypothalamic leptin actions, which maintains survival during food shortages. In inducible liver insulin receptor knockout mice, body weight is increased with hyperphagia and decreased energy expenditure, accompanied by increased circulating leptin receptor (LepR) and decreased hypothalamic leptin actions. Additional hepatic LepR deficiency reverses these metabolic phenotypes. Thus, decreased hepatic insulin action suppresses hypothalamic leptin action with increased liver-derived soluble LepR. Human hepatic and circulating LepR levels also correlate negatively with hepatic insulin action indices. In mice, food restriction decreases hepatic insulin action and energy expenditure with increased circulating LepR. Hepatic LepR deficiency increases mortality with enhanced energy expenditure during food restriction. The liver translates metabolic cues regarding energy-deficient status, which is reflected by decreased hepatic insulin action, into soluble LepR, thereby suppressing energy dissipation and assuring survival during food shortages.
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Affiliation(s)
- Kei Takahashi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Tetsuya Yamada
- Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-8510, Japan.
| | - Shinichiro Hosaka
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Keizo Kaneko
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Yoichiro Asai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Yuichiro Munakata
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Junro Seike
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Takahiro Horiuchi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Shinjiro Kodama
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Tomohito Izumi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Shojiro Sawada
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Kyoko Hoshikawa
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Yamagata 990-9585, Japan
| | - Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Yamagata 990-9585, Japan
| | - Junta Imai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan.
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11
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Krokowski D, Jobava R, Szkop KJ, Chen CW, Fu X, Venus S, Guan BJ, Wu J, Gao Z, Banaszuk W, Tchorzewski M, Mu T, Ropelewski P, Merrick WC, Mao Y, Sevval AI, Miranda H, Qian SB, Manifava M, Ktistakis NT, Vourekas A, Jankowsky E, Topisirovic I, Larsson O, Hatzoglou M. Stress-induced perturbations in intracellular amino acids reprogram mRNA translation in osmoadaptation independently of the ISR. Cell Rep 2022; 40:111092. [PMID: 35858571 PMCID: PMC9491157 DOI: 10.1016/j.celrep.2022.111092] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 04/26/2022] [Accepted: 06/22/2022] [Indexed: 12/23/2022] Open
Abstract
The integrated stress response (ISR) plays a pivotal role in adaptation of translation machinery to cellular stress. Here, we demonstrate an ISR-independent osmoadaptation mechanism involving reprogramming of translation via coordinated but independent actions of mTOR and plasma membrane amino acid transporter SNAT2. This biphasic response entails reduced global protein synthesis and mTOR signaling followed by translation of SNAT2. Induction of SNAT2 leads to accumulation of amino acids and reactivation of mTOR and global protein synthesis, paralleled by partial reversal of the early-phase, stress-induced translatome. We propose SNAT2 functions as a molecular switch between inhibition of protein synthesis and establishment of an osmoadaptive translation program involving the formation of cytoplasmic condensates of SNAT2-regulated RNA-binding proteins DDX3X and FUS. In summary, we define key roles of SNAT2 in osmotolerance.
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Affiliation(s)
- Dawid Krokowski
- Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Molecular Biology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Lublin, Poland.
| | - Raul Jobava
- Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Krzysztof J Szkop
- Department of Oncology-Pathology, Science for Life Laboratories, Karolinska Institute, Stockholm, Sweden
| | - Chien-Wen Chen
- Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Xu Fu
- Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Sarah Venus
- Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Bo-Jhih Guan
- Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Jing Wu
- Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Zhaofeng Gao
- Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Wioleta Banaszuk
- Department of Molecular Biology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Lublin, Poland
| | - Marek Tchorzewski
- Department of Molecular Biology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Lublin, Poland; EcoTech-Complex Centre, Maria Curie-Skłodowska University, Lublin, Poland
| | - Tingwei Mu
- Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Phil Ropelewski
- Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - William C Merrick
- Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Yuanhui Mao
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Aksoylu Inci Sevval
- Department of Oncology-Pathology, Science for Life Laboratories, Karolinska Institute, Stockholm, Sweden
| | - Helen Miranda
- Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Shu-Bing Qian
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
| | | | | | - Anastasios Vourekas
- Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA
| | - Eckhard Jankowsky
- Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Ivan Topisirovic
- The Lady Davis Institute, Jewish General Hospital, Montréal, QC, Canada; Gerald Bronfman Department of Oncology, McGill University, Montréal, QC, Canada; Department of Biochemistry and Division of Experimental Medicine, McGill University, Montréal, QC, Canada.
| | - Ola Larsson
- Department of Oncology-Pathology, Science for Life Laboratories, Karolinska Institute, Stockholm, Sweden.
| | - Maria Hatzoglou
- Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
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12
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Chi ZC. Metabolic associated fatty liver disease is a disease related to sympathetic nervous system activation. Shijie Huaren Xiaohua Zazhi 2022; 30:465-476. [DOI: 10.11569/wcjd.v30.i11.465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Strong evidence from animal and human studies shows that sympathetic nervous system (SNS) activation is a key factor in the development of metabolic associated fatty liver disease (MAFLD). Activation of the sympathetic nervous system plays an important role in the pathogenesis of obesity, metabolic syndrome, diabetes, hypertension, and MAFLD. When genetically susceptible subjects are exposed to a variety of epigenetic changes, their liver damage may develop into MAFLD. Thus, the pathogenesis of MAFLD is complex, involving the complex interaction of insulin resistance, abnormal hormone secretion, obesity, diet, genetic factors, immune activation, gut microbiota, and other factors. In these processes, the role of sympathetic nerves cannot be underestimated. Notably, SNS has been proposed as a therapeutic target for MAFLD by inhibiting sympathetic nerves. It is worthy of further discussion and research.
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Affiliation(s)
- Zhao-Chun Chi
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
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13
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Yan S, Chen J, Zhu L, Guo T, Qin D, Hu Z, Han S, Zhou Y, Akan OD, Wang J, Luo F, Lin Q. Oryzanol Attenuates High Fat and Cholesterol Diet-Induced Hyperlipidemia by Regulating the Gut Microbiome and Amino Acid Metabolism. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2022; 70:6429-6443. [PMID: 35587527 DOI: 10.1021/acs.jafc.2c00885] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Hyperlipidemia is intricately associated with the dysregulation of gut microbiota and host metabolomes. This study explored the antihyperlipidemic function of oryzanol and investigated whether the function of oryzanol affected the gut microbiome and its related metabolites. Hamsters were fed a standard diet (Control) and a high fat and cholesterol (HFCD) diet with or without oryzanol, separately. Our results showed that oryzanol significantly decreased HFCD-induced fat accumulation, serum total cholesterol, low-density lipoprotein cholesterol (LDL-c), LDL-c/HDL-c ratio, triglyceride, and liver steatohepatitis, attenuated HFCD-induced gut microbiota alterations, and altered amino acid concentrations in feces and the liver. We investigated the role of the gut microbiota in the observed beneficial effects; the protective effects of oryzanol were partly diminished by suppressing the gut bacteria of hamsters after using antibiotics. A fecal microbiota transplantation experiment was carried out by transplanting the feces from HFCD group hamsters or hamsters given oryzanol supplementation (as a donor hamster). Our results showed that administering the fecal liquid from oryzanol-treated hamsters attenuated HFCD-induced hyperlipidemia, significantly decreased the abundance of norank_f__Erysipelotrichaceae, norank_f__Eubacteriaceae, and norank_f__Oscillospiraceae and the concentration of tyrosine. These outcomes are significantly positively correlated with serum lipid concentration. This study illustrated that gut microbiota is the target of oryzanol in the antihyperlipidemic effect.
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Affiliation(s)
- Sisi Yan
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
| | - Jihong Chen
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Lingfeng Zhu
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Tianyi Guo
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Dandan Qin
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Zuomin Hu
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Shuai Han
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Yaping Zhou
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Otobang Donald Akan
- National Engineering Laboratory for Deep Process of Rice and Byproducts, College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha 410004, China
| | - Ji Wang
- Hunan Engineering Research Center of Livestock and Poultry Health Care, Colleges of Veterinary Medicine, Hunan Agricultural University, Changsha 410128, China
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14
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Calpain-mediated proteolytic production of free amino acids in vascular endothelial cells augments obesity-induced hepatic steatosis. J Biol Chem 2022; 298:101953. [PMID: 35447117 PMCID: PMC9110893 DOI: 10.1016/j.jbc.2022.101953] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 04/02/2022] [Accepted: 04/04/2022] [Indexed: 10/25/2022] Open
Abstract
Free amino acids that accumulate in the plasma of diabetes and obesity patients influence lipid metabolism and protein synthesis in the liver. The stress-inducible intracellular protease calpain proteolyzes various substrates in vascular endothelial cells (ECs), although its contribution to the supply of free amino acids in the liver microenvironment remains enigmatic. In the present study, we showed that calpains are associated with free amino acid production in cultured ECs. Furthermore, conditioned media derived from calpain-activated ECs facilitated the phosphorylation of ribosomal protein S6 kinase (S6K) and de novo lipogenesis in hepatocytes, which were abolished by the amino acid transporter inhibitor, JPH203, and the mTORC1 inhibitor, rapamycin. Meanwhile, calpain-overexpressing capillary-like ECs were observed in the livers of high-fat diet-fed mice. Conditional knockout of EC/hematopoietic Capns1, which encodes a calpain regulatory subunit, diminished levels of branched chain amino acids in the hepatic microenvironment without altering plasma amino acid levels. Concomitantly, conditional knockout of Capns1 mitigated hepatic steatosis without normalizing body weight and the plasma lipoprotein profile in an amino acid transporter-dependent manner. Mice with targeted Capns1 knockout exhibited reduced phosphorylation of S6K and maturation of lipid homeostasis transcription factor SREBP1 in hepatocytes. Finally, we show that bone marrow transplantation negated the contribution of hematopoietic calpain systems; therefore, calpains are likely responsible for the observed phenotypes of ECs. We conclude that overactivation of calpain systems may be responsible for the production of free amino acid in ECs, which may be sufficient to potentiate S6K/SREBP1-induced lipogenesis in surrounding hepatocytes.
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15
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Isacco CG, Nguyen KC, Pham VH, Di Palma G, Aityan SK, Tomassone D, Distratis P, Lazzaro R, Balzanelli MG, Inchingolo F. Bone decay and diabetes type 2 in searching for a link. Endocr Metab Immune Disord Drug Targets 2022; 22:904-910. [PMID: 35331127 DOI: 10.2174/1871530322666220324150327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 01/17/2022] [Accepted: 02/02/2022] [Indexed: 11/22/2022]
Affiliation(s)
- Ciro Gargiulo Isacco
- Department of Interdisciplinary Medicine (D.I.M.) of Bari University of Medicine Aldo Moro, Bari City Italy
| | - Kieu Cd Nguyen
- 118 Pre-Hospital and Emergency Department, SG Moscati Hospital, ASL Taranto, Italy
| | - Van H Pham
- Phan Chau Trinh University of Medicine Hoi An City Vietnam
| | - Gianna Di Palma
- Department of Interdisciplinary Medicine (D.I.M.) of Bari University of Medicine Aldo Moro, Bari City Italy
| | | | - Diego Tomassone
- Foundation of Physics Research Center (FoPRC), Celico-CS, Italy
| | - Pietro Distratis
- 118 Pre-Hospital and Emergency Department, SG Moscati Hospital, ASL Taranto, Italy
| | - Rita Lazzaro
- 118 Pre-Hospital and Emergency Department, SG Moscati Hospital, ASL Taranto, Italy
| | - Mario G Balzanelli
- 118 Pre-Hospital and Emergency Department, SG Moscati Hospital, ASL Taranto, Italy
| | - Francesco Inchingolo
- Department of Interdisciplinary Medicine (D.I.M.) of Bari University of Medicine Aldo Moro, Bari City Italy
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16
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Du C, Yang W, Yu Z, Yuan Q, Pang D, Tang P, Jiang W, Chen M, Xiao B. Rheb Promotes Triglyceride Secretion and Ameliorates Diet-Induced Steatosis in the Liver. Front Cell Dev Biol 2022; 10:808140. [PMID: 35372326 PMCID: PMC8965806 DOI: 10.3389/fcell.2022.808140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 02/21/2022] [Indexed: 11/13/2022] Open
Abstract
Hepatosteatosis, characterized by excessive accumulation of lipids in the liver, is a major health issue in modern society. Understanding how altered hepatic lipid metabolism/homeostasis causes hepatosteatosis helps to develop therapeutic interventions. Previous studies identify mitochondrial dysfunction as a contributor to hepatosteatosis. But, the molecular mechanisms of mitochondrial dysfunction leading to altered lipid metabolism remain incompletely understood. Our previous work shows that Rheb, a Ras-like small GTPase, not only activates mTORC1 but also promotes mitochondrial ATP production through pyruvate dehydrogenase (PDH). In this study, we further demonstrate that Rheb controls hepatic triglyceride secretion and reduces diet-induced lipid accumulation in a mouse liver. Genetic deletion of Rheb causes rapid and spontaneous steatosis in the liver, which is unexpected from the role of mTORC1 that enhances lipid synthesis, whereas Rheb transgene remarkably reduces diet-induced hepatosteatosis. Results suggest that the hepatosteatosis in Rheb KO is an outcome of impaired lipid secretion, which is linked to mitochondrial ATP production of hepatocytes. Our findings highlight an under-appreciated role of Rheb in the regulation of hepatic lipid secretion through mitochondrial energy production, with therapeutic implication.
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Affiliation(s)
- Chongyangzi Du
- Neuroscience and Metabolism Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wanchun Yang
- Neuroscience and Metabolism Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China
| | - Zongyan Yu
- Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
- Department of Biology, School of Life Sciences, Brain Research Center, Southern University of Science and Technology, Shenzhen, China
| | - Qiuyun Yuan
- Neuroscience and Metabolism Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Dejiang Pang
- Neuroscience and Metabolism Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Ping Tang
- Neuroscience and Metabolism Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wanxiang Jiang
- Neuroscience and Metabolism Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Mina Chen
- Neuroscience and Metabolism Research, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
- Correspondence: Bo Xiao, ; Mina Chen, .
| | - Bo Xiao
- Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, China
- Department of Biology, School of Life Sciences, Brain Research Center, Southern University of Science and Technology, Shenzhen, China
- Correspondence: Bo Xiao, ; Mina Chen, .
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17
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p70 S6 kinase as a therapeutic target in cancers: More than just an mTOR effector. Cancer Lett 2022; 535:215593. [PMID: 35176419 DOI: 10.1016/j.canlet.2022.215593] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 01/25/2022] [Accepted: 02/06/2022] [Indexed: 11/23/2022]
Abstract
p70 S6 kinase (p70S6K) is best-known for its regulatory roles in protein synthesis and cell growth by phosphorylating its primary substrate, ribosomal protein S6, upon mitogen stimulation. The enhanced expression/activation of p70S6K has been correlated with poor prognosis in some cancer types, suggesting that it may serve as a biomarker for disease monitoring. p70S6K is a critical downstream effector of the oncogenic PI3K/Akt/mTOR pathway and its activation is tightly regulated by an ordered cascade of Ser/Thr phosphorylation events. Nonetheless, it should be noted that other upstream mechanisms regulating p70S6K at both the post-translational and post-transcriptional levels also exist. Activated p70S6K could promote various aspects of cancer progression such as epithelial-mesenchymal transition, cancer stemness and drug resistance. Importantly, novel evidence showing that p70S6K may also regulate different cellular components in the tumor microenvironment will be discussed. Therapeutic targeting of p70S6K alone or in combination with traditional chemotherapies or other microenvironmental-based drugs such as immunotherapy may represent promising approaches against cancers with aberrant p70S6K signaling. Currently, the only clinically available p70S6K inhibitors are rapamycin analogs (rapalogs) which target mTOR. However, there are emerging p70S6K-selective drugs which are going through active preclinical or clinical trial phases. Moreover, various screening strategies have been used for the discovery of novel p70S6K inhibitors, hence bringing new insights for p70S6K-targeted therapy.
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18
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Matsubara Y, Kiyohara H, Teratani T, Mikami Y, Kanai T. Organ and brain crosstalk: The liver-brain axis in gastrointestinal, liver, and pancreatic diseases. Neuropharmacology 2021; 205:108915. [PMID: 34919906 DOI: 10.1016/j.neuropharm.2021.108915] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 12/01/2021] [Accepted: 12/06/2021] [Indexed: 12/15/2022]
Abstract
The liver is the largest organ in the human body and is responsible for the metabolism and storage of the three principal nutrients: carbohydrates, fats, and proteins. In addition, the liver contributes to the breakdown and excretion of alcohol, medicinal agents, and toxic substances and the production and secretion of bile. In addition to its role as a metabolic centre, the liver has recently attracted attention for its function in the liver-brain axis, which interacts closely with the central nervous system via the autonomic nervous system, including the vagus nerve. The liver-brain axis influences the control of eating behaviour in the central nervous system through stimuli from the liver. Conversely, neural signals from the central nervous system influence glucose, lipid, and protein metabolism in the liver. The liver also receives a constant influx of nutrients and hormones from the intestinal tract and compounds of bacterial origin via the portal system. As a result, the intestinal tract and liver are involved in various immunological interactions. A good example is the co-occurrence of primary sclerosing cholangitis and ulcerative colitis. These heterogeneous roles of the liver-brain axis are mediated via the vagus nerve in an asymmetrical manner. In this review, we provide an overview of these interactions, mainly with the liver but also with the brain and gut.
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Affiliation(s)
- Yuta Matsubara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Hiroki Kiyohara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Toshiaki Teratani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Yohei Mikami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, 100-0004, Japan.
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19
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Narimatsu Y, Fukumura K, Iwakoshi-Ukena E, Mimura A, Furumitsu M, Ukena K. Subcutaneous infusion of neurosecretory protein GL promotes fat accumulation in mice. Heliyon 2021; 7:e07502. [PMID: 34296011 PMCID: PMC8282975 DOI: 10.1016/j.heliyon.2021.e07502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 04/21/2021] [Accepted: 07/03/2021] [Indexed: 11/19/2022] Open
Abstract
We recently identified a novel small secretory protein, neurosecretory protein GL (NPGL), in the vertebrate hypothalamus. We revealed that NPGL is involved in energy homeostasis using intracerebroventricular infusion in rodents. However, the effect of NPGL through peripheral administration remains to be elucidated and may be important for therapeutic use. In this study, we performed subcutaneous infusion of NPGL in mice for 12 days and found that it accelerated fat accumulation in white adipose tissue (WAT) without increasing in body mass gain and food intake. The mass of the testis, liver, kidney, heart, and gastrocnemius muscle remained unchanged. Analysis of mRNA expression by quantitative reverse transcription-polymerase chain reaction showed that proopiomelanocortin was suppressed in the hypothalamus by the infusion of NPGL. We observed a decreasing tendency in serum triglyceride levels due to NPGL, while serum glucose, insulin, leptin, and free fatty acids levels were unchanged. These results suggest that the peripheral administration of NPGL induces fat accumulation in WAT via the hypothalamus.
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20
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Imai J, Katagiri H. Regulation of systemic metabolism by the autonomic nervous system consisting of afferent and efferent innervation. Int Immunol 2021; 34:67-79. [PMID: 33982088 DOI: 10.1093/intimm/dxab023] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 05/10/2021] [Indexed: 12/18/2022] Open
Abstract
Autonomic nerves, sympathetic and parasympathetic, innervate organs and modulate their functions. It has become evident that afferent and efferent signals of the autonomic nervous system play important roles in regulating systemic metabolism, thereby maintaining homeostasis at the whole-body level. Vagal afferent nerves receive signals, such as nutrients and hormones, from the peripheral organs/tissues including the gastrointestinal tract and adipose tissue then transmit these signals to the hypothalamus, thereby regulating feeding behavior. In addition to roles in controlling appetite, areas in the hypothalamus serves as regulatory centers of both sympathetic and parasympathetic efferent fibers. These efferent innervations regulate the functions of peripheral organs/tissues, such as pancreatic islets, adipose tissues and the liver, which play roles in metabolic regulation. Furthermore, recent evidence has unraveled the metabolic regulatory systems governed by autonomic nerve circuits. In these systems, afferent nerves transmit metabolic information from peripheral organs to the central nervous system (CNS) and the CNS thereby regulates the organ functions through the efferent fibers of autonomic nerves. Thus, the autonomic nervous system regulates the homeostasis of systemic metabolism, and both afferent and efferent fibers play critical roles in its regulation. In addition, several lines of evidence demonstrate the roles of the autonomic nervous system in regulating and dysregulating the immune system. This review introduces variety of neuron-mediated inter-organ cross-talk systems and organizes the current knowledge of autonomic control/coordination of systemic metabolism, focusing especially on a liver-brain-pancreatic β-cell autonomic nerve circuit, as well as highlighting the potential importance of connections with the neuronal and immune systems.
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Affiliation(s)
- Junta Imai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan
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21
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Mizuno K, Haga H, Okumoto K, Hoshikawa K, Katsumi T, Nishina T, Saito T, Katagiri H, Ueno Y. Intrahepatic distribution of nerve fibers and alterations due to fibrosis in diseased liver. PLoS One 2021; 16:e0249556. [PMID: 33852613 PMCID: PMC8046205 DOI: 10.1371/journal.pone.0249556] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 03/21/2021] [Indexed: 01/23/2023] Open
Abstract
Autonomic nerve fibers in the liver are distributed along the portal tract, being involved in the regulation of blood flow, bile secretion and hepatic metabolism, thus contributing to systemic homeostasis. The present study investigated changes in hepatic nerve fibers in liver biopsy specimens from patients with normal liver, viral hepatitis and non-alcoholic steatohepatitis, in relation to clinical background. The areal ratio of nerve fibers to the total portal area was automatically calculated for each sample. The nerve fiber areal ratios (NFAR) for total nerve fibers and sympathetic nerve fibers were significantly lower in liver affected by chronic hepatitis, particularly viral hepatitis, and this was also the case for advanced liver fibrosis. However, the degree of inflammatory activity did not affect NFAR for either whole nerves or sympathetic nerves. Comparison of samples obtained before and after antiviral treatment for HCV demonstrated recovery of NFAR along with improvement of liver fibrosis.
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Affiliation(s)
- Kei Mizuno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
- Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
| | - Hiroaki Haga
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
- Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
| | - Kazuo Okumoto
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Kyoko Hoshikawa
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
- Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
| | - Tomohiro Katsumi
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
- Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
| | - Taketo Nishina
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
- Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
| | - Takafumi Saito
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
- Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (CREST), Tokyo, Japan
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22
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Wu LZ, Weng YQ, Ling YX, Zhou SJ, Ding XK, Wu SQ, Yu K, Jiang SF, Chen Y. A Web of Science-based scientometric analysis about mammalian target of rapamycin signaling pathway in kidney disease from 1986 to 2020. Transl Androl Urol 2021; 10:1006-1017. [PMID: 33850735 PMCID: PMC8039620 DOI: 10.21037/tau-20-1469] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Background The mammalian target of rapamycin (mTOR) signaling pathway is vital for the regulation of cell metabolism, growth and proliferation in the kidney. This study aims to show current research focuses and predict future trends about mTOR pathway in kidney disease by the methods of scientometric analysis. Methods We referred to publications from the Web of ScienceTM Core Collection (WoSCC) Database. Carrot2, VOSviewer and CiteSpace programs were applied to evaluate the distribution and contribution of authors, institutes and countries/regions of extensive bibliographic metadata, show current research focuses and predict future trends in kidney disease's area. Results Until July 10, 2020, there are 2,585 manuscripts about mTOR signaling pathway in kidney disease in total and every manuscript is cited 27.39 times on average. The big name of course is the United States. Research hot spots include "diabetic nephropathy", "kidney transplantation", "autosomal dominant polycystic kidney disease", "tuberous sclerosis complex", "renal cell carcinoma" and "autophagy". Seven key clusters are detected, including "kidney transplantation", "autosomal dominant polycystic kidney disease", "renal transplantation", "renal cell carcinoma", "hamartin", "autophagy" and "tuberous sclerosis complex". Conclusions Diabetic nephropathy, kidney transplantation, autosomal dominant polycystic kidney disease, tuberous sclerosis complex, renal cell carcinoma and autophagy are future research hot spots by utilizing scientometric analysis. In the future, it is necessary to research these fields.
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Affiliation(s)
- Lian-Zhong Wu
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Wenzhou Medical University, Wenzhou, China
| | - Yi-Qin Weng
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Wenzhou Medical University, Wenzhou, China
| | - Yi-Xin Ling
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Wenzhou Medical University, Wenzhou, China
| | - Shu-Juan Zhou
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao-Kai Ding
- Department of Nephrology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Si-Qi Wu
- Wenzhou Medical University, Wenzhou, China
| | - Kang Yu
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Song-Fu Jiang
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yi Chen
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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23
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The liver-brain-gut neural arc maintains the T reg cell niche in the gut. Nature 2020; 585:591-596. [PMID: 32526765 DOI: 10.1038/s41586-020-2425-3] [Citation(s) in RCA: 162] [Impact Index Per Article: 32.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 06/04/2020] [Indexed: 02/07/2023]
Abstract
Recent clinical and experimental evidence has evoked the concept of the gut-brain axis to explain mutual interactions between the central nervous system and gut microbiota that are closely associated with the bidirectional effects of inflammatory bowel disease and central nervous system disorders1-4. Despite recent advances in our understanding of neuroimmune interactions, it remains unclear how the gut and brain communicate to maintain gut immune homeostasis, including in the induction and maintenance of peripheral regulatory T cells (pTreg cells), and what environmental cues prompt the host to protect itself from development of inflammatory bowel diseases. Here we report a liver-brain-gut neural arc that ensures the proper differentiation and maintenance of pTreg cells in the gut. The hepatic vagal sensory afferent nerves are responsible for indirectly sensing the gut microenvironment and relaying the sensory inputs to the nucleus tractus solitarius of the brainstem, and ultimately to the vagal parasympathetic nerves and enteric neurons. Surgical and chemical perturbation of the vagal sensory afferents at the hepatic afferent level reduced the abundance of colonic pTreg cells; this was attributed to decreased aldehyde dehydrogenase (ALDH) expression and retinoic acid synthesis by intestinal antigen-presenting cells. Activation of muscarinic acetylcholine receptors directly induced ALDH gene expression in both human and mouse colonic antigen-presenting cells, whereas genetic ablation of these receptors abolished the stimulation of antigen-presenting cells in vitro. Disruption of left vagal sensory afferents from the liver to the brainstem in mouse models of colitis reduced the colonic pTreg cell pool, resulting in increased susceptibility to colitis. These results demonstrate that the novel vago-vagal liver-brain-gut reflex arc controls the number of pTreg cells and maintains gut homeostasis. Intervention in this autonomic feedback feedforward system could help in the development of therapeutic strategies to treat or prevent immunological disorders of the gut.
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24
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Oishi Y, Manabe I. Organ System Crosstalk in Cardiometabolic Disease in the Age of Multimorbidity. Front Cardiovasc Med 2020; 7:64. [PMID: 32411724 PMCID: PMC7198858 DOI: 10.3389/fcvm.2020.00064] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 03/27/2020] [Indexed: 12/11/2022] Open
Abstract
The close association among cardiovascular, metabolic, and kidney diseases suggests a common pathological basis and significant interaction among these diseases. Metabolic syndrome and cardiorenal syndrome are two examples that exemplify the interlinked development of disease or dysfunction in two or more organs. Recent studies have been sorting out the mechanisms responsible for the crosstalk among the organs comprising the cardiovascular, metabolic, and renal systems, including heart-kidney and adipose-liver signaling, among many others. However, it is also becoming clear that this crosstalk is not limited to just pairs of organs, and in addition to organ-organ crosstalk, there are also organ-system and organ-body interactions. For instance, heart failure broadly impacts various organs and systems, including the kidney, liver, lung, and nervous system. Conversely, systemic dysregulation of metabolism, immunity, and nervous system activity greatly affects heart failure development and prognosis. This is particularly noteworthy, as more and more patients present with two or more coexisting chronic diseases or conditions (multimorbidity) due in part to the aging of society. Advances in treatment also contribute to the increase in multimorbidity, as exemplified by cardiovascular disease in cancer survivors. To understand the mechanisms underlying the increasing burden of multimorbidity, it is vital to elucidate the multilevel crosstalk and communication within the body at the levels of organ systems, tissues, and cells. In this article, we focus on chronic inflammation as a key common pathological basis of cardiovascular and metabolic diseases, and discuss emerging mechanisms that drive chronic inflammation in the context of multimorbidity.
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Affiliation(s)
- Yumiko Oishi
- Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan
| | - Ichiro Manabe
- Department of Disease Biology and Molecular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan
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25
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Fang J, Pan L, Gu QX, Juengpanich S, Zheng JH, Tong CH, Wang ZY, Nan JJ, Wang YF. Scientometric analysis of mTOR signaling pathway in liver disease. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:93. [PMID: 32175386 DOI: 10.21037/atm.2019.12.110] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background The mTOR pathway is vital for homeostasis, metabolism, cancer transplantation and regeneration in the liver. The aim of this study is to use a bibliometric method to reveal current research hotspots and promising future trends in mTOR signaling in liver diseases. Methods Publications were searched and downloaded from the Web of Science Core Collection (WOSCC) Database. CiteSpace, Carrot2, and VOSviewer programs were utilized to analyze the contribution of various countries/regions, institutes, and authors; and to reveal research hotspots and promising future trends in this research area. Results Until May 21, 2019, a total of 2,232 papers regarding mTOR signaling pathway in liver disease were included, and each paper was cited 23.21 times on average. The most active country was the USA. 5 landmark articles with centrality and burstiness were determined by co-citation analysis. Research hotspots included "liver transplantation" "hepatic stellate cell proliferation" "NAFLD" "therapy of HCC". Moreover, six key clusters were discovered during the procedure of "clustering", including "liver transplantation" "protein synthesis" "mTOR inhibitor" "following early cyclosporine withdrawal" "srebp-1 activation", and "hepatocellular cancer". Conclusions Various scientific methods were applied to reveal scientific productivity, collaboration, and research hotspots in the mTOR signaling pathway in liver disease. Liver transplantation, hepatic stellate cell proliferation, non-alcoholic fatty liver disease (NAFLD), therapy of hepatocellular carcinoma (HCC), cell growth and autophagy, are research hotspots and are likely to be promising in the next few years. Further studies in this field are needed.
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Affiliation(s)
- Jing Fang
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
| | - Long Pan
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
| | - Qiu-Xia Gu
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
| | - Sarun Juengpanich
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
| | - Jun-Hao Zheng
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
| | - Chen-Hao Tong
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Department of General Surgery, Shaoxing People's Hospital, Zhejiang University School of Medicine, Shaoxing 312000, China
| | - Zi-Yuan Wang
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China
| | - Jun-Jie Nan
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China
| | - Yi-Fan Wang
- Key Laboratory of Laparoscopic Technique Research of Zhejiang Province, Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China.,Zhejiang Province Medical Research Center of Minimally Invasive Diagnosis and Treatment of Abdominal Diseases, Hangzhou 310016, China.,Institute of Minimally Invasive Surgery of Zhejiang University, Hangzhou 310016, China
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26
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Menchini RJ, Chaudhry FA. Multifaceted regulation of the system A transporter Slc38a2 suggests nanoscale regulation of amino acid metabolism and cellular signaling. Neuropharmacology 2019; 161:107789. [PMID: 31574264 DOI: 10.1016/j.neuropharm.2019.107789] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 09/16/2019] [Accepted: 09/20/2019] [Indexed: 02/07/2023]
Abstract
Amino acids are essential for cellular protein synthesis, growth, metabolism, signaling and in stress responses. Cell plasma membranes harbor specialized transporters accumulating amino acids to support a variety of cellular biochemical pathways. Several transporters for neutral amino acids have been characterized. However, Slc38a2 (also known as SA1, SAT2, ATA2, SNAT2) representing the classical transport system A activity stands in a unique position: Being a secondarily active transporter energized by the electrochemical gradient of Na+, it creates steep concentration gradients for amino acids such as glutamine: this may subsequently drive the accumulation of additional neutral amino acids through exchange via transport systems ASC and L. Slc38a2 is ubiquitously expressed, yet in a cell-specific manner. In this review, we show that Slc38a2 is regulated at the transcriptional and translational levels as well as by ions and proteins through direct interactions. We describe how Slc38a2 senses amino acid availability and passes this onto intracellular signaling pathways and how it regulates protein synthesis, cellular proliferation and apoptosis through the mechanistic (mammalian) target of rapamycin (mTOR) and general control nonderepressible 2 (GCN2) pathways. Furthermore, we review how this extensively regulated transporter contributes to cellular osmoadaptation and how it is regulated by endoplasmic reticulum stress and various hormonal stimuli to promote cellular metabolism, cellular signaling and cell survival. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.
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Affiliation(s)
| | - Farrukh Abbas Chaudhry
- Department of Molecular Medicine, University of Oslo, Oslo, Norway; Department of Plastic and Reconstructive Surgery, Oslo University Hospital, Oslo, Norway
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27
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Fasterius E, Uhlén M, Al-Khalili Szigyarto C. Single-cell RNA-seq variant analysis for exploration of genetic heterogeneity in cancer. Sci Rep 2019; 9:9524. [PMID: 31267007 PMCID: PMC6606766 DOI: 10.1038/s41598-019-45934-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 06/20/2019] [Indexed: 01/23/2023] Open
Abstract
Inter- and intra-tumour heterogeneity is caused by genetic and non-genetic factors, leading to severe clinical implications. High-throughput sequencing technologies provide unprecedented tools to analyse DNA and RNA in single cells and explore both genetic heterogeneity and phenotypic variation between cells in tissues and tumours. Simultaneous analysis of both DNA and RNA in the same cell is, however, still in its infancy. We have thus developed a method to extract and analyse information regarding genetic heterogeneity that affects cellular biology from single-cell RNA-seq data. The method enables both comparisons and clustering of cells based on genetic variation in single nucleotide variants, revealing cellular subpopulations corroborated by gene expression-based methods. Furthermore, the results show that lymph node metastases have lower levels of genetic heterogeneity compared to their original tumours with respect to variants affecting protein function. The analysis also revealed three previously unknown variants common across cancer cells in glioblastoma patients. These results demonstrate the power and versatility of scRNA-seq variant analysis and highlight it as a useful complement to already existing methods, enabling simultaneous investigations of both gene expression and genetic variation.
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Affiliation(s)
- Erik Fasterius
- School of Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Mathias Uhlén
- School of Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden.,Science for Life Laboratory, KTH Royal Institute of Technology, Solna, Sweden
| | - Cristina Al-Khalili Szigyarto
- School of Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, Stockholm, Sweden. .,Science for Life Laboratory, KTH Royal Institute of Technology, Solna, Sweden.
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28
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Amino acid transporters in the regulation of insulin secretion and signalling. Biochem Soc Trans 2019; 47:571-590. [PMID: 30936244 DOI: 10.1042/bst20180250] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 02/24/2019] [Accepted: 02/25/2019] [Indexed: 01/02/2023]
Abstract
Amino acids are increasingly recognised as modulators of nutrient disposal, including their role in regulating blood glucose through interactions with insulin signalling. More recently, cellular membrane transporters of amino acids have been shown to form a pivotal part of this regulation as they are primarily responsible for controlling cellular and circulating amino acid concentrations. The availability of amino acids regulated by transporters can amplify insulin secretion and modulate insulin signalling in various tissues. In addition, insulin itself can regulate the expression of numerous amino acid transporters. This review focuses on amino acid transporters linked to the regulation of insulin secretion and signalling with a focus on those of the small intestine, pancreatic β-islet cells and insulin-responsive tissues, liver and skeletal muscle. We summarise the role of the amino acid transporter B0AT1 (SLC6A19) and peptide transporter PEPT1 (SLC15A1) in the modulation of global insulin signalling via the liver-secreted hormone fibroblast growth factor 21 (FGF21). The role of vesicular vGLUT (SLC17) and mitochondrial SLC25 transporters in providing glutamate for the potentiation of insulin secretion is covered. We also survey the roles SNAT (SLC38) family and LAT1 (SLC7A5) amino acid transporters play in the regulation of and by insulin in numerous affective tissues. We hypothesise the small intestine amino acid transporter B0AT1 represents a crucial nexus between insulin, FGF21 and incretin hormone signalling pathways. The aim is to give an integrated overview of the important role amino acid transporters have been found to play in insulin-regulated nutrient signalling.
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29
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Stretton C, Lipina C, Hyde R, Cwiklinski E, Hoffmann TM, Taylor PM, Hundal HS. CDK7 is a component of the integrated stress response regulating SNAT2 (SLC38A2)/System A adaptation in response to cellular amino acid deprivation. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2019; 1866:978-991. [PMID: 30857869 PMCID: PMC6456927 DOI: 10.1016/j.bbamcr.2019.03.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 03/04/2019] [Accepted: 03/06/2019] [Indexed: 12/31/2022]
Abstract
Extracellular amino acid (AA) withdrawal/restriction invokes an integrated stress response (ISR) that induces global suppression of protein synthesis whilst allowing transcription and translation of a select group of genes, whose protein products facilitate cellular adaptation to AA insufficiency. Transcriptional induction of the System A/SNAT2 AA transporter represents a classic adaptation response and crucially depends upon activation of the General Control Nonderepressible-2 kinase/Activating transcription factor 4 (GCN2/ATF4) pathway. However, the ISR may also include additional signalling inputs operating in conjunction or independently of GCN2/ATF4 to upregulate SNAT2. Herein, we show that whilst pharmacological inhibition of MEK-ERK, mTORC1 and p38 MAP kinase signalling has no detectable effect on System A upregulation, inhibitors targeting GSK3 (e.g. SB415286) caused significant repression of the SNAT2 adaptation response. Strikingly, the effects of SB415286 persist in cells in which GSK3α/β have been stably silenced indicating an off-target effect. We show that SB415286 can also inhibit cyclin-dependent kinases (CDK) and that roscovitine and flavopiridol (two pan CDK inhibitors) are effective repressors of the SNAT2 adaptive response. In particular, our work reveals that CDK7 activity is upregulated in AA-deprived cells in a GCN-2-dependent manner and that a potent and selective CDK7 inhibitor, THZ-1, not only attenuates the increase in ATF4 expression but blocks System A adaptation. Importantly, the inhibitory effects of THZ-1 on System A adaptation are mitigated in cells expressing a doxycycline-inducible drug-resistant form of CDK7. Our data identify CDK7 as a novel component of the ISR regulating System A adaptation in response to AA insufficiency.
Roscovitine and flavopiridol (CDK inhibitors) block the System A adaptive response. Extracellular amino acid (AA) withdrawal induces CDK7 activation. Pharmacological inhibition of GCN2 represses CDK7 activation in AA-deprived cells. Targeted suppression of CDK7 represses ATF4 expression and System A adaptation.
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Affiliation(s)
- Clare Stretton
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
| | - Christopher Lipina
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
| | - Russell Hyde
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
| | - Emma Cwiklinski
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
| | - Thorsten M Hoffmann
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
| | - Peter M Taylor
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
| | - Harinder S Hundal
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
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30
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Gancheva S, Jelenik T, Álvarez-Hernández E, Roden M. Interorgan Metabolic Crosstalk in Human Insulin Resistance. Physiol Rev 2018; 98:1371-1415. [PMID: 29767564 DOI: 10.1152/physrev.00015.2017] [Citation(s) in RCA: 138] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Excessive energy intake and reduced energy expenditure drive the development of insulin resistance and metabolic diseases such as obesity and type 2 diabetes mellitus. Metabolic signals derived from dietary intake or secreted from adipose tissue, gut, and liver contribute to energy homeostasis. Recent metabolomic studies identified novel metabolites and enlarged our knowledge on classic metabolites. This review summarizes the evidence of their roles as mediators of interorgan crosstalk and regulators of insulin sensitivity and energy metabolism. Circulating lipids such as free fatty acids, acetate, and palmitoleate from adipose tissue and short-chain fatty acids from the gut effectively act on liver and skeletal muscle. Intracellular lipids such as diacylglycerols and sphingolipids can serve as lipotoxins by directly inhibiting insulin action in muscle and liver. In contrast, fatty acid esters of hydroxy fatty acids have been recently shown to exert a series of beneficial effects. Also, ketoacids are gaining interest as potent modulators of insulin action and mitochondrial function. Finally, branched-chain amino acids not only predict metabolic diseases, but also inhibit insulin signaling. Here, we focus on the metabolic crosstalk in humans, which regulates insulin sensitivity and energy homeostasis in the main insulin-sensitive tissues, skeletal muscle, liver, and adipose tissue.
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Affiliation(s)
- Sofiya Gancheva
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University , Düsseldorf , Germany ; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University , Düsseldorf , Germany ; and German Center of Diabetes Research (DZD e.V.), Munich- Neuherberg , Germany
| | - Tomas Jelenik
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University , Düsseldorf , Germany ; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University , Düsseldorf , Germany ; and German Center of Diabetes Research (DZD e.V.), Munich- Neuherberg , Germany
| | - Elisa Álvarez-Hernández
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University , Düsseldorf , Germany ; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University , Düsseldorf , Germany ; and German Center of Diabetes Research (DZD e.V.), Munich- Neuherberg , Germany
| | - Michael Roden
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University , Düsseldorf , Germany ; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University , Düsseldorf , Germany ; and German Center of Diabetes Research (DZD e.V.), Munich- Neuherberg , Germany
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Ali M, Bukhari SA, Ali M, Lee HW. Upstream signalling of mTORC1 and its hyperactivation in type 2 diabetes (T2D). BMB Rep 2018; 50:601-609. [PMID: 29187279 PMCID: PMC5749905 DOI: 10.5483/bmbrep.2017.50.12.206] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Indexed: 12/19/2022] Open
Abstract
Mammalian target of rapamycin complex 1 (mTORC1) plays a major role in cell growth, proliferation, polarity, differentiation, development, and controls transitioning between anabolic and catabolic states of the cell. It collects almost all extracellular and intracellular signals from growth factors, nutrients, and maintains cellular homeostasis, and is involved in several pathological conditions including, neurodegeneration, Type 2 diabetes (T2D), obesity, and cancer. In this review, we summarize current knowledge of upstream signaling of mTORC1 to explain etiology of T2D and hypertriglyceridemia, in which state, the role of telomere attrition is explained. We discuss if chronic inhibition of mTORC1 can reverse adverse effects resulting from hyperactivation. In conclusion, we suggest the regulatory roles of telomerase (TERT) and hexokinase II (HKII) on mTORC1 as possible remedies to treat hyperactivation. The former inhibits mTORC1 under nutrient-rich while the latter under starved condition. We provide an idea of TOS (TOR signaling) motifs that can be used for regulation of mTORC1.
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Affiliation(s)
- Muhammad Ali
- Departments of Biochemistry, Government College University, Faisalabad, 38000 Pakistan
| | - Shazia Anwer Bukhari
- Departments of Biochemistry, Government College University, Faisalabad, 38000 Pakistan
| | - Muhammad Ali
- Departments of Zoology, Government College University, Faisalabad, 38000 Pakistan
| | - Han-Woong Lee
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
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Xu K, Liu G, Fu C. The Tryptophan Pathway Targeting Antioxidant Capacity in the Placenta. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:1054797. [PMID: 30140360 PMCID: PMC6081554 DOI: 10.1155/2018/1054797] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 06/26/2018] [Indexed: 12/19/2022]
Abstract
The placenta plays a vital role in fetal development during pregnancy. Dysfunction of the placenta can be caused by oxidative stress and can lead to abnormal fetal development. Preventing oxidative stress of the placenta is thus an important measure to ensure positive birth outcomes. Research shows that tryptophan and its metabolites can efficiently clean free radicals (including the reactive oxygen species and activated chlorine). Consequently, tryptophan and its metabolites are suggested to act as potent antioxidants in the placenta. However, the mechanism of these antioxidant properties in the placenta is still unknown. In this review, we summarize research on the antioxidant properties of tryptophan, tryptophan metabolites, and metabolic enzymes. Two predicted mechanisms of tryptophan's antioxidant properties are discussed. (1) Tryptophan could activate the phosphorylation of p62 after the activation of mTORC1; phosphorylated p62 then uncouples the interaction between Nrf2 and Keap1, and activated Nrf2 enters the nucleus to induce expressions of antioxidant proteins, thus improving cellular antioxidation. (2) 3-Hydroxyanthranilic acid, a tryptophan kynurenine pathway metabolite, changes conformation of Keap1, inducing the dissociation of Nrf2 and Keap1, activating Nrf2 to enter the nucleus and induce expressions of antioxidant proteins (such as HO-1), thereby enhancing cellular antioxidant capacity. These mechanisms may enrich the theory of how to apply tryptophan as an antioxidant during pregnancy, providing technical support for its use in regulating the pregnancy's redox status and enriching our understanding of amino acids' nutritional value.
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Affiliation(s)
- Kang Xu
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Changsha, Hunan 410125, China
| | - Gang Liu
- Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Changsha, Hunan 410125, China
| | - Chenxing Fu
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, Hunan 410128, China
- Hunan Collaborative Innovation Center for Utilization of Botanical Functional Ingredients and Hunan Collaborative Innovation Center of Animal Production Safety, Changsha, Hunan 410128, China
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Hoffmann TM, Cwiklinski E, Shah DS, Stretton C, Hyde R, Taylor PM, Hundal HS. Effects of Sodium and Amino Acid Substrate Availability upon the Expression and Stability of the SNAT2 (SLC38A2) Amino Acid Transporter. Front Pharmacol 2018; 9:63. [PMID: 29467657 PMCID: PMC5808304 DOI: 10.3389/fphar.2018.00063] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 01/17/2018] [Indexed: 12/14/2022] Open
Abstract
The SNAT2 (SLC38A2) System A amino acid transporter mediates Na+-coupled cellular uptake of small neutral α-amino acids (AAs) and is extensively regulated in response to humoral and nutritional cues. Understanding the basis of such regulation is important given that AA uptake via SNAT2 has been linked to activation of mTORC1; a major controller of many important cellular processes including, for example, mRNA translation, lipid synthesis, and autophagy and whose dysregulation has been implicated in the development of cancer and conditions such as obesity and type 2 diabetes. Extracellular AA withdrawal induces an adaptive upregulation of SNAT2 gene transcription and SNAT2 protein stability but, as yet, the sensing mechanism(s) that initiate this response remain poorly understood although interactions between SNAT2 and its substrates may play a vital role. Herein, we have explored how changes in substrate (AA and Na+) availability impact upon the adaptive regulation of SNAT2 in HeLa cells. We show that while AA deprivation induces SNAT2 gene expression, this induction was not apparent if extracellular Na+ was removed during the AA withdrawal period. Furthermore, we show that the increase in SNAT2 protein stability associated with AA withdrawal is selectively repressed by provision of SNAT2 AA substrates (N-methylaminoisobutyric acid and glutamine), but not non-substrates. This stabilization and substrate-induced repression were critically dependent upon the cytoplasmic N-terminal tail of SNAT2 (containing lysyl residues which are putative targets of the ubiquitin-proteasome system), because “grafting” this tail onto SNAT5, a related SLC38 family member that does not exhibit adaptive regulation, confers substrate-induced changes in stability of the SNAT2-5 chimeric transporter. In contrast, expression of SNAT2 in which the N-terminal lysyl residues were mutated to alanine rendered the transporter stable and insensitive to substrate-induced changes in protein stability. Intriguingly, SNAT2 protein stability was dramatically reduced in the absence of extracellular Na+ irrespective of whether substrate AAs were present or absent. Our findings indicate that the presence of extracellular Na+ (and potentially its binding to SNAT2) may be crucial for not only sensing SNAT2 AA occupancy and consequently for initiating the adaptive response under AA insufficient conditions, but for enabling substrate-induced changes in SNAT2 protein stability.
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Affiliation(s)
- Thorsten M Hoffmann
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, United Kingdom
| | - Emma Cwiklinski
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, United Kingdom
| | - Dinesh S Shah
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, United Kingdom
| | - Clare Stretton
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, United Kingdom
| | - Russell Hyde
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, United Kingdom
| | - Peter M Taylor
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, United Kingdom
| | - Harinder S Hundal
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, United Kingdom
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Sawada Y, Izumida Y, Takeuchi Y, Aita Y, Wada N, Li E, Murayama Y, Piao X, Shikama A, Masuda Y, Nishi-Tatsumi M, Kubota M, Sekiya M, Matsuzaka T, Nakagawa Y, Sugano Y, Iwasaki H, Kobayashi K, Yatoh S, Suzuki H, Yagyu H, Kawakami Y, Kadowaki T, Shimano H, Yahagi N. Effect of sodium-glucose cotransporter 2 (SGLT2) inhibition on weight loss is partly mediated by liver-brain-adipose neurocircuitry. Biochem Biophys Res Commun 2017; 493:40-45. [PMID: 28928093 DOI: 10.1016/j.bbrc.2017.09.081] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Accepted: 09/15/2017] [Indexed: 01/06/2023]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have both anti-diabetic and anti-obesity effects. However, the precise mechanism of the anti-obesity effect remains unclear. We previously demonstrated that the glycogen depletion signal triggers lipolysis in adipose tissue via liver-brain-adipose neurocircuitry. In this study, therefore, we investigated whether the anti-obesity mechanism of SGLT2 inhibitor is mediated by this mechanism. Diet-induced obese mice were subjected to hepatic vagotomy (HVx) or sham operation and loaded with high fat diet containing 0.015% tofogliflozin (TOFO), a highly selective SGLT2 inhibitor, for 3 weeks. TOFO-treated mice showed a decrease in fat mass and the effect of TOFO was attenuated in HVx group. Although both HVx and sham mice showed a similar level of reduction in hepatic glycogen by TOFO treatment, HVx mice exhibited an attenuated response in protein phosphorylation by protein kinase A (PKA) in white adipose tissue compared with the sham group. As PKA pathway is known to act as an effector of the liver-brain-adipose axis and activate triglyceride lipases in adipocytes, these results indicated that SGLT2 inhibition triggered glycogen depletion signal and actuated liver-brain-adipose axis, resulting in PKA activation in adipocytes. Taken together, it was concluded that the effect of SGLT2 inhibition on weight loss is in part mediated via the liver-brain-adipose neurocircuitry.
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Affiliation(s)
- Yoshikazu Sawada
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Yoshihiko Izumida
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan
| | - Yoshinori Takeuchi
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Yuichi Aita
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Nobuhiro Wada
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan
| | - EnXu Li
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan
| | - Yuki Murayama
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Xianying Piao
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Akito Shikama
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Yukari Masuda
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan
| | - Makiko Nishi-Tatsumi
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Midori Kubota
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan
| | - Motohiro Sekiya
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Takashi Matsuzaka
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Yoshimi Nakagawa
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Yoko Sugano
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Hitoshi Iwasaki
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Kazuto Kobayashi
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Shigeru Yatoh
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Hiroaki Suzuki
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Hiroaki Yagyu
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Yasushi Kawakami
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Takashi Kadowaki
- Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan
| | - Hitoshi Shimano
- Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan
| | - Naoya Yahagi
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki, 305-8575, Japan; Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan.
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35
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Caputo T, Gilardi F, Desvergne B. From chronic overnutrition to metaflammation and insulin resistance: adipose tissue and liver contributions. FEBS Lett 2017; 591:3061-3088. [DOI: 10.1002/1873-3468.12742] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 06/28/2017] [Accepted: 07/02/2017] [Indexed: 12/16/2022]
Affiliation(s)
- Tiziana Caputo
- Center for Integrative Genomics; Lausanne Faculty of Biology and Medicine; University of Lausanne; Switzerland
| | - Federica Gilardi
- Center for Integrative Genomics; Lausanne Faculty of Biology and Medicine; University of Lausanne; Switzerland
| | - Béatrice Desvergne
- Center for Integrative Genomics; Lausanne Faculty of Biology and Medicine; University of Lausanne; Switzerland
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Moran-Ramos S, Ocampo-Medina E, Gutierrez-Aguilar R, Macías-Kauffer L, Villamil-Ramírez H, López-Contreras BE, León-Mimila P, Vega-Badillo J, Gutierrez-Vidal R, Villarruel-Vazquez R, Serrano-Carbajal E, Del-Río-Navarro BE, Huertas-Vázquez A, Villarreal-Molina T, Ibarra-Gonzalez I, Vela-Amieva M, Aguilar-Salinas CA, Canizales-Quinteros S. An Amino Acid Signature Associated with Obesity Predicts 2-Year Risk of Hypertriglyceridemia in School-Age Children. Sci Rep 2017; 7:5607. [PMID: 28717206 PMCID: PMC5514079 DOI: 10.1038/s41598-017-05765-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 06/02/2017] [Indexed: 01/21/2023] Open
Abstract
Childhood obesity is associated with a number of metabolic abnormalities leading to increased cardiovascular risk. Metabolites can be useful as early biomarkers and new targets to promote early intervention beginning in school age. Thus, we aimed to identify metabolomic profiles associated with obesity and obesity-related metabolic traits. We used data from the Obesity Research Study for Mexican children (ORSMEC) in Mexico City and included a case control (n = 1120), cross-sectional (n = 554) and a longitudinal study (n = 301) of 6-12-year-old children. Forty-two metabolites were measured using electrospray MS/MS and multivariate regression models were used to test associations of metabolomic profiles with anthropometric, clinical and biochemical parameters. Principal component analysis showed a serum amino acid signature composed of arginine, leucine/isoleucine, phenylalanine, tyrosine, valine and proline significantly associated with obesity (OR = 1.57; 95%CI 1.45-1.69, P = 3.84 × 10-31) and serum triglycerides (TG) (β = 0.067, P = 4.5 × 10-21). These associations were validated in the cross-sectional study (P < 0.0001). In the longitudinal cohort, the amino acid signature was associated with serum TG and with the risk of hypertriglyceridemia after 2 years (OR = 1.19; 95%CI 1.03-1.39, P = 0.016). This study shows that an amino acid signature significantly associated with childhood obesity, is an independent risk factor of future hypertriglyceridemia in children.
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Affiliation(s)
- Sofia Moran-Ramos
- Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico City, Mexico.
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico.
| | - Elvira Ocampo-Medina
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | - Ruth Gutierrez-Aguilar
- Hospital Infantil México Federico Gómez, Mexico City, Mexico
- Facultad de Medicina, UNAM, Mexico City, Mexico
| | - Luis Macías-Kauffer
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | - Hugo Villamil-Ramírez
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | - Blanca E López-Contreras
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | - Paola León-Mimila
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | - Joel Vega-Badillo
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | - Roxana Gutierrez-Vidal
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | - Ricardo Villarruel-Vazquez
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | - Erandi Serrano-Carbajal
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico
| | | | | | | | - Isabel Ibarra-Gonzalez
- Instituto de Investigaciones Biomédicas, UNAM - Instituto Nacional de Pediatría, Mexico City, Mexico
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Mexico City, Mexico
| | - Marcela Vela-Amieva
- Laboratorio de Errores Innatos del Metabolismo y Tamiz, Instituto Nacional de Pediatría, Mexico City, Mexico
| | - Carlos A Aguilar-Salinas
- Departamento de Endocrinología y Metabolismo, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Samuel Canizales-Quinteros
- Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico.
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Yamada D, Koppensteiner P, Odagiri S, Eguchi M, Yamaguchi S, Yamada T, Katagiri H, Wada K, Sekiguchi M. Common Hepatic Branch of Vagus Nerve-Dependent Expression of Immediate Early Genes in the Mouse Brain by Intraportal L-Arginine: Comparison with Cholecystokinin-8. Front Neurosci 2017; 11:366. [PMID: 28701913 PMCID: PMC5487424 DOI: 10.3389/fnins.2017.00366] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 06/12/2017] [Indexed: 12/22/2022] Open
Abstract
Information from the peripheral organs is thought to be transmitted to the brain by humoral factors and neurons such as afferent vagal or spinal nerves. The common hepatic branch of the vagus (CHBV) is one of the main vagus nerve branches, and consists of heterogeneous neuronal fibers that innervate multiple peripheral organs such as the bile duct, portal vein, paraganglia, and gastroduodenal tract. Although, previous studies suggested that the CHBV has a pivotal role in transmitting information on the status of the liver to the brain, the details of its central projections remain unknown. The purpose of the present study was to investigate the brain regions activated by the CHBV. For this purpose, we injected L-arginine or anorexia-associated peptide cholecystokinin-8 (CCK), which are known to increase CHBV electrical activity, into the portal vein of transgenic Arc-dVenus mice expressing the fluorescent protein Venus under control of the activity-regulated cytoskeleton-associated protein (Arc) promotor. The brain slices were prepared from these mice and the number of Venus positive cells in the slices was counted. After that, c-Fos expression in these slices was analyzed by immunohistochemistry using the avidin-biotin-peroxidase complex method. Intraportal administration of L-arginine increased the number of Venus positive or c-Fos positive cells in the insular cortex. This action of L-arginine was not observed in CHBV-vagotomized Arc-dVenus mice. In contrast, intraportal administration of CCK did not increase the number of c-Fos positive or Venus positive cells in the insular cortex. Intraportal CCK induced c-Fos expression in the dorsomedial hypothalamus, while intraportal L-arginine did not. This action of CCK was abolished by CHBV vagotomy. Intraportal L-arginine reduced, while intraportal CCK increased, the number of c-Fos positive cells in the nucleus tractus solitarii in a CHBV-dependent manner. The present results suggest that the CHBV can activate different brain regions depending on the nature of the peripheral stimulus.
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Affiliation(s)
- Daisuke Yamada
- Department of Degenerative Neurological Diseases, National Center of Neurology and Psychiatry, National Institute of NeuroscienceTokyo, Japan
| | - Peter Koppensteiner
- Department of Degenerative Neurological Diseases, National Center of Neurology and Psychiatry, National Institute of NeuroscienceTokyo, Japan
| | - Saori Odagiri
- Department of Degenerative Neurological Diseases, National Center of Neurology and Psychiatry, National Institute of NeuroscienceTokyo, Japan
| | - Megumi Eguchi
- Department of Morphological Neuroscience, Graduate School of Medicine, Gifu UniversityGifu, Japan
| | - Shun Yamaguchi
- Department of Morphological Neuroscience, Graduate School of Medicine, Gifu UniversityGifu, Japan.,Center for Highly Advanced Integration of Nano and Life Sciences, Gifu UniversityGifu, Japan.,Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology AgencySaitama, Japan
| | - Tetsuya Yamada
- Department of Metabolism and Diabetes, Graduate School of Medicine, Tohoku UniversityMiyagi, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Graduate School of Medicine, Tohoku UniversityMiyagi, Japan.,CREST, Japan Agency for Medical Research and DevelopmentTokyo, Japan
| | - Keiji Wada
- Department of Degenerative Neurological Diseases, National Center of Neurology and Psychiatry, National Institute of NeuroscienceTokyo, Japan.,CREST, Japan Agency for Medical Research and DevelopmentTokyo, Japan
| | - Masayuki Sekiguchi
- Department of Degenerative Neurological Diseases, National Center of Neurology and Psychiatry, National Institute of NeuroscienceTokyo, Japan
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López-Soldado I, Fuentes-Romero R, Duran J, Guinovart JJ. Effects of hepatic glycogen on food intake and glucose homeostasis are mediated by the vagus nerve in mice. Diabetologia 2017; 60:1076-1083. [PMID: 28299379 DOI: 10.1007/s00125-017-4240-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 02/14/2017] [Indexed: 10/20/2022]
Abstract
AIMS/HYPOTHESIS Liver glycogen plays a key role in regulating food intake and blood glucose. Mice that accumulate large amounts of this polysaccharide in the liver are protected from high-fat diet (HFD)-induced obesity by reduced food intake. Furthermore, these animals show reversal of the glucose intolerance and hyperinsulinaemia caused by the HFD. The aim of this study was to examine the involvement of the hepatic branch of the vagus nerve in regulating food intake and glucose homeostasis in this model. METHODS We performed hepatic branch vagotomy (HBV) or a sham operation on mice overexpressing protein targeting to glycogen (Ptg OE). Starting 1 week after surgery, mice were fed an HFD for 10 weeks. RESULTS HBV did not alter liver glycogen or ATP levels, thereby indicating that this procedure does not interfere with hepatic energy balance. However, HBV reversed the effect of glycogen accumulation on food intake. In wild-type mice, HBV led to a significant reduction in body weight without a change in food intake. Consistent with their body weight reduction, these animals had decreased fat deposition, adipocyte size, and insulin and leptin levels, together with increased energy expenditure. Ptg OE mice showed an increase in energy expenditure and glucose oxidation, and these differences were abolished by HBV. Moreover, Ptg OE mice showed an improvement in HFD-induced glucose intolerance, which was suppressed by HBV. CONCLUSIONS/INTERPRETATION Our results demonstrate that the regulation of food intake and glucose homeostasis by liver glycogen is dependent on the hepatic branch of the vagus nerve.
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Affiliation(s)
- Iliana López-Soldado
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Rebeca Fuentes-Romero
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028, Barcelona, Spain
| | - Jordi Duran
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Joan J Guinovart
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028, Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain.
- Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Barcelona, Spain.
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Abstract
PURPOSE OF REVIEW Hepatic lipid and lipoprotein metabolism is an important determinant of fasting dyslipidemia and the development of fatty liver disease. Although endocrine factors like insulin have known effects on hepatic lipid homeostasis, emerging evidence also supports a regulatory role for the central nervous system (CNS) and neuronal networks. This review summarizes evidence implicating a bidirectional liver-brain axis in maintaining metabolic lipid homeostasis, and discusses clinical implications in insulin-resistant states. RECENT FINDINGS The liver utilizes sympathetic and parasympathetic afferent and efferent fibers to communicate with key regulatory centers in the brain including the hypothalamus. Hypothalamic anorexigenic and orexigenic peptides signal to the liver via neuronal networks to modulate lipid content and VLDL production. In addition, peripheral hormones such as insulin, leptin, and glucagon-like-peptide-1 exert control over hepatic lipid by acting directly within the CNS or via peripheral nerves. Central regulation of lipid metabolism in other organs including white and brown adipose tissue may also contribute to hepatic lipid content indirectly via free fatty acid release and changes in lipoprotein clearance. SUMMARY The CNS communicates with the liver in a bidirectional manner to regulate hepatic lipid metabolism and lipoprotein production. Impairments in these pathways may contribute to dyslipidemia and hepatic steatosis in insulin-resistant states.
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Affiliation(s)
- Jennifer Taher
- aDepartment of Laboratory Medicine and Pathobiology, University of Toronto bMolecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
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40
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Abstract
Although the human liver comprises approximately 2.8% of the body weight, it plays a central role in the control of energy metabolism. While the biochemistry of energy substrates such as glucose, fatty acids, and ketone bodies in the liver is well understood, many aspects of the overall control system for hepatic metabolism remain largely unknown. These include mechanisms underlying the ascertainment of its energy metabolism status by the liver, and the way in which this information is used to communicate and function together with adipose tissues and other organs involved in energy metabolism. This review article summarizes hepatic control of energy metabolism via the autonomic nervous system.
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Affiliation(s)
- Naoya Yahagi
- Nutrigenomics Research Group, Faculty of Medicine, University of Tsukuba
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41
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Roles of the interorgan neuronal network in the development of metabolic syndrome. Diabetol Int 2016; 7:205-211. [PMID: 30603265 DOI: 10.1007/s13340-016-0277-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 06/26/2016] [Indexed: 01/01/2023]
Abstract
Metabolic processes in different tissues and remote organs are under coordinated systemic regulation, allowing adaptation to a variety of external circumstances. Neuronal signals as well as humoral factors, such as nutrients, growth factors, and hormones, have attracted increasing attention for their roles in this interorgan metabolic network, responsible for the maintenance of metabolic homeostasis at the whole-body level. These interorgan communications within an organism are considered to be diverse and, in fact, we identified previously unknown neuronal relay systems originating in the liver which modulate energy, glucose, and lipid metabolism. Furthermore, when nutrient overload is prolonged, these neuronal mechanisms, which function as an endogenous defense system against obesity development, contribute to the pathophysiological states of metabolic syndrome characterized by obesity-associated features. Therefore, these interorgan neuronal systems are considered to be possible molecular targets for treating metabolic syndrome. We herein review the precise mechanisms underlying the functions of the mammalian interorgan neuronal network, especially the pathways from the liver to several other organs, focusing on their significance and roles in the development of metabolic syndrome.
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Rubio-Aliaga I, Wagner CA. Regulation and function of the SLC38A3/SNAT3 glutamine transporter. Channels (Austin) 2016; 10:440-52. [PMID: 27362266 DOI: 10.1080/19336950.2016.1207024] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Affiliation(s)
- Isabel Rubio-Aliaga
- a Institute of Physiology, the National Center for Competence in Research NCCR Kidney, University of Zurich , Zurich , Switzerland
| | - Carsten A Wagner
- a Institute of Physiology, the National Center for Competence in Research NCCR Kidney, University of Zurich , Zurich , Switzerland
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43
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Abstract
PURPOSE OF REVIEW A major step in energy metabolism is hydrolysis of triacylglycerol-rich lipoproteins (TRLs) to release fatty acids that can be used or stored. This is accomplished by lipoprotein lipase (LPL) at 'binding lipolysis sites' at the vascular endothelium. A multitude of interactions are involved in this seemingly simple reaction. Recent advances in the understanding of some of these factors will be discussed in an attempt to build a comprehensive picture. RECENT FINDINGS The first event in catabolism of TRLs is that they dock at the vascular endothelium. This requires LPL and GPIHBP1, the endothelial transporter of LPL.Kinetic studies in rats with labeled chylomicrons showed that once a chylomicron has docked in the heart it stays for minutes and a large number of triacylglycerol molecules are split. The distribution of binding between tissues reflects the amount of LPL, as evident from studies with mutant mice.Clearance of TRLs is often slowed down in metabolic disease, as was demonstrated both in mice and men. In mice, this was directly connected to decreased amounts of endothelial LPL. SUMMARY The LPL system is central in energy metabolism and results from interplay between several factors. Rapid and exciting progress is being made.
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Affiliation(s)
- Gunilla Olivecrona
- Department of Medical Biosciences/Physiological Chemistry, Umeå University, Umeå, Sweden
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44
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Chiba Y, Yamada T, Tsukita S, Takahashi K, Munakata Y, Shirai Y, Kodama S, Asai Y, Sugisawa T, Uno K, Sawada S, Imai J, Nakamura K, Katagiri H. Dapagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor, Acutely Reduces Energy Expenditure in BAT via Neural Signals in Mice. PLoS One 2016; 11:e0150756. [PMID: 26963613 PMCID: PMC4786146 DOI: 10.1371/journal.pone.0150756] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 02/17/2016] [Indexed: 12/19/2022] Open
Abstract
Selective sodium glucose cotransporter-2 inhibitor (SGLT2i) treatment promotes urinary glucose excretion, thereby reducing blood glucose as well as body weight. However, only limited body weight reductions are achieved with SGLT2i treatment. Hyperphagia is reportedly one of the causes of this limited weight loss. However, the effects of SGLT2i treatment on systemic energy expenditure have not been fully elucidated. Herein, we investigated the acute effects of dapagliflozin, a SGLT2i, on systemic energy expenditure in mice. Eighteen hours after dapagliflozin treatment oxygen consumption and brown adipose tissue (BAT) expression of ucp1, a thermogenesis-related gene, were significantly decreased as compared to those after vehicle treatment. In addition, dapagliflozin significantly suppressed norepinephrine (NE) turnover in BAT and c-fos expression in the rostral raphe pallidus nucleus (rRPa) which contains the sympathetic premotor neurons responsible for thermogenesis. These findings indicate that the dapagliflozin-mediated acute decrease in energy expenditure involves a reduction in BAT thermogenesis via decreased sympathetic nerve activity from the rRPa. Furthermore, common hepatic branch vagotomy abolished the reductions in ucp1 expression and NE contents in BAT and c-fos expression in the rRPa. In addition, alterations in hepatic carbohydrate metabolism, such as decreases in glycogen contents and upregulation of phosphoenolpyruvate carboxykinase, manifested prior to the suppression of BAT thermogenesis, e.g. 6 hours after dapagliflozin treatment. Collectively, these results suggest that SGLT2i treatment acutely suppresses energy expenditure in BAT via regulation of an inter-organ neural network consisting of the common hepatic vagal branch and sympathetic nerves.
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Affiliation(s)
- Yumiko Chiba
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Tetsuya Yamada
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
- * E-mail:
| | - Sohei Tsukita
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Kei Takahashi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Yuichiro Munakata
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Yuta Shirai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Shinjiro Kodama
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Yoichiro Asai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Takashi Sugisawa
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Kenji Uno
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Shojiro Sawada
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Junta Imai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
| | - Kazuhiro Nakamura
- Department of Integrative Physiology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
- Japan Agency for Medical Research and Development (AMED), CREST, Sendai, 980-8575, Japan
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45
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Zhou D, Wang Y, Chen L, Jia L, Yuan J, Sun M, Zhang W, Wang P, Zuo J, Xu Z, Luan J. Evolving roles of circadian rhythms in liver homeostasis and pathology. Oncotarget 2016; 7:8625-39. [PMID: 26843619 PMCID: PMC4890992 DOI: 10.18632/oncotarget.7065] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 01/18/2016] [Indexed: 02/06/2023] Open
Abstract
Circadian clock in mammals is determined by a core oscillator in the suprachiasmatic nucleus (SCN) of the hypothalamus and synchronized peripheral clocks in other tissues. The coherent timing systems could sustain robust output of circadian rhythms in response to the entrainment controlled environmentally. Disparate approaches have discovered that clock genes and clock-controlled genes (CCGs) exist in nearly all mammalian cell types and are essential for establishing the mechanisms and complexity of internal time-keeping systems. Accumulating evidence demonstrates that the control of homeostasis and pathology in the liver involves intricate loops of transcriptional and post-translational regulation of clock genes expression. This review will focus on the recent advances with great importance concerning clock rhythms linking liver homeostasis and diseases. We particularly highlight what is currently known of the evolving insights into the mechanisms underlying circadian clock . Eventually , findings during recent years in the field might prompt new circadian-related chronotherapeutic strategies for the diagnosis and treatment of liver diseases by coupling these processes.
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Affiliation(s)
- Dexi Zhou
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Yaqin Wang
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Lu Chen
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Leijuan Jia
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Jie Yuan
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Mei Sun
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Wen Zhang
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Peipei Wang
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Jian Zuo
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Zhenyu Xu
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
| | - Jiajie Luan
- Laboratory of Clinical Pharmacy of Wannan Medical College, Wuhu, Anhui Province, China
- Department of Pharmacy in Yijishan Hospital of Wannan Medical College, Wuhu, Anhui Province, China
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Zhou X, Guo J, Ji Y, Pan G, Liu T, Zhu H, Zhao J. Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma. Mol Cancer Res 2016; 14:448-57. [PMID: 26896556 DOI: 10.1158/1541-7786.mcr-15-0480] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Accepted: 02/10/2016] [Indexed: 11/16/2022]
Affiliation(s)
- Xuefeng Zhou
- Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China
| | - Jialong Guo
- Department of Cardiothoracic Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, P.R. China
| | - Yanmei Ji
- Department of Intensive Care Unit, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, P.R. China
| | - Gaofeng Pan
- Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China
| | - Tao Liu
- Department of Cardiothoracic Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, P.R. China
| | - Hua Zhu
- Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio.
| | - Jinping Zhao
- Department of Thoracic and Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, P.R. China.
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Cai H, Dong LQ, Liu F. Recent Advances in Adipose mTOR Signaling and Function: Therapeutic Prospects. Trends Pharmacol Sci 2015; 37:303-317. [PMID: 26700098 DOI: 10.1016/j.tips.2015.11.011] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Revised: 11/19/2015] [Accepted: 11/20/2015] [Indexed: 12/11/2022]
Abstract
The increasing epidemic of obesity and its comorbidities has spurred research interest in adipose biology and its regulatory functions. Recent studies have revealed that the mechanistic target of rapamycin (mTOR) signaling pathway has a critical role in the regulation of adipose tissue function, including adipogenesis, lipid metabolism, thermogenesis, and adipokine synthesis and/or secretion. Given the importance of mTOR signaling in controlling energy homeostasis, it is not unexpected that deregulated mTOR signaling is associated with obesity and related metabolic disorders. In this review, we highlight current advances in understanding the roles of the mTOR signaling pathway in adipose tissue. We also provide a more nuanced view of how the mTOR signaling pathway regulates adipose tissue biology and function. Finally, we describe approaches to modulate the activity and tissue-specific function of mTOR that may pave the way towards counteracting obesity and related metabolic diseases.
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Affiliation(s)
- Huan Cai
- Institute of Metabolism and Endocrinology, Metabolic Syndrome Research Center, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Department of Pharmacology, UTHSCSA, San Antonio, TX, USA
| | - Lily Q Dong
- Departments of Cellular Structural Biology, UTHSCSA, San Antonio, TX, USA
| | - Feng Liu
- Institute of Metabolism and Endocrinology, Metabolic Syndrome Research Center, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Department of Pharmacology, UTHSCSA, San Antonio, TX, USA.
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48
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Yu G, Huang B, Chen G, Mi Y. Phosphatidylethanolamine-binding protein 4 promotes lung cancer cells proliferation and invasion via PI3K/Akt/mTOR axis. J Thorac Dis 2015; 7:1806-16. [PMID: 26623104 PMCID: PMC4635298 DOI: 10.3978/j.issn.2072-1439.2015.10.17] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 10/11/2015] [Indexed: 01/17/2023]
Abstract
BACKGROUND While phosphatidylethanolamine-binding protein 4 (PEBP4) is a key factor in the malignant proliferation and metastasis of tumor cells, the exact regulatory network governing its roles remains unclear. This study was designed to investigate the effect of PEBP4 on PI3K/Akt/mTOR pathway and explore its molecular network that governs the proliferation and metastasis of tumor cells. METHODS After the recombinant plasmid pcDNA3.1-PEBP4 was constructed, the recombinant plasmid pcDNA3.1-PEBP4 and PEBP4-targeting siRNA were transfected into lung cancer HCC827 cell line. The expressions of PI3K/Akt/mTOR pathway components in HCC827 cells in each group were determined using Western blotting. In the HCC827 cells, the effect of PI3K pathway inhibitor LY294002 on the expressions of PI3K/Akt/mTOR pathway components under the effect of PEBP4 was determined using Western blotting, and the effects of LY294002 on the cell viability, proliferation, and migration capabilities under the overexpression of PEBP4 were determined using MTT method, flow cytometry, and Transwell migration assay. Furthermore, the effect of mTOR inhibitor rapamycin (RAPA) on the expressions of PI3K/Akt/mTOR pathway components under the effect of PEBP4 was determined using Western blotting, and the effects of RAPA on the cell viability, proliferation, and migration capabilities under the overexpression of PEBP4 were determined using MTT method, flow cytometry, and Transwell migration assay. RESULTS As shown by Western blotting, the protein expressions of p-Akt and phosphorylated mTOR (p-mTOR) were significantly higher in the pcDNA3.1-PEBP4-transfected group than in the normal control group and PEBP4 siRNA group (P<0.05); furthermore, the protein expressions of p-Akt and p-mTOR significantly decreased in the PEBP4 targeting siRNA-transfected group (P<0.05). Treatment with LY294002 significantly inhibited the protein expressions of p-Akt and p-mTOR in HCC827 cells (P<0.05). In contrast, treatment with RAPA only significantly inhibited the protein expression of p-mTOR (P<0.05). As shown by MTT, flow cytometry, and Transwell migration assay, both LY294002 and RAPA could significantly lower the viability of HCC827 cells and inhibit their proliferation and invasion (P<0.05); meanwhile, they could reverse the effect of PEBP4 in promoting the proliferation and migration of HCC827 cells (P<0.05). CONCLUSIONS The overexpression of PEBP4 increases the phosphorylation levels of Akt and mTOR in lung cancer cells. The PI3K/Akt/mTOR signaling axis may be a key molecular pathway via which PEBP4 promotes the proliferation and invasion of non-small cell lung cancer (NSCLC) cells; also, it may serve as a potential therapeutic target.
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Affiliation(s)
- Guiping Yu
- Department of Cardiothoracic Surgery, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin 214400, China
| | - Bin Huang
- Department of Cardiothoracic Surgery, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin 214400, China
| | - Guoqiang Chen
- Department of Cardiothoracic Surgery, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin 214400, China
| | - Yedong Mi
- Department of Cardiothoracic Surgery, The Affiliated Jiangyin Hospital of Southeast University Medical College, Jiangyin 214400, China
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