Vitamin D ameliorates age-induced nonalcoholic fatty liver disease by increasing the mitochondrial contact site and cristae organizing system (MICOS) 60 level
0
조회
0
다운로드
0
인용
0
참고문헌
초록
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease. Despite intensive research, considerable information on NAFLD development remains elusive. In this study, we examined the effects of vitamin D on age-induced NAFLD, especially in connection with mitochondrial abnormalities. We observed the prevention of NAFLD in 22-month-old C57BL/6 mice fed a vitamin D3-supplemented (20,000 IU/kg) diet compared with mice fed a control (1000 IU/kg) diet. We evaluated whether vitamin D3 supplementation enhanced mitochondrial functions. We found that the level of mitochondrial contact site and cristae organizing system (MICOS) 60 (Mic60) level was reduced in aged mice, and this reduction was specifically restored by vitamin D3. In addition, depletion of Immt, the human gene encoding the Mic60 protein, induced changes in gene expression patterns that led to fat accumulation in both HepG2 and primary hepatocytes, and these alterations were effectively prevented by vitamin D3. In addition, silencing of the vitamin D receptor (VDR) decreased the Mic60 levels, which were recovered by vitamin D treatment. To assess whether VDR directly regulates Mic60 levels, we performed chromatin immunoprecipitation and reporter gene analysis. We discovered that VDR directly binds to the Immt 5’ promoter region spanning positions −3157 to −2323 and thereby upregulates Mic60. Our study provides the first demonstration that a reduction in Mic60 levels due to aging may be one of the mechanisms underlying the development of aging-associated NAFLD. In addition, vitamin D3 could positively regulate Mic60 expression, and this may be one of the important mechanisms by which vitamin D could ameliorate age-induced NAFLD.
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease. Despite intensive research, considerable information on NAFLD development remains elusive. In this study, we examined the effects of vitamin D on age-induced NAFLD, especially in connection with mitochondrial abnormalities. We observed the prevention of NAFLD in 22-month-old C57BL/6 mice fed a vitamin D3-supplemented (20,000 IU/kg) diet compared with mice fed a control (1000 IU/kg) diet. We evaluated whether vitamin D3 supplementation enhanced mitochondrial functions. We found that the level of mitochondrial contact site and cristae organizing system (MICOS) 60 (Mic60) level was reduced in aged mice, and this reduction was specifically restored by vitamin D3. In addition, depletion of Immt, the human gene encoding the Mic60 protein, induced changes in gene expression patterns that led to fat accumulation in both HepG2 and primary hepatocytes, and these alterations were effectively prevented by vitamin D3. In addition, silencing of the vitamin D receptor (VDR) decreased the Mic60 levels, which were recovered by vitamin D treatment. To assess whether VDR directly regulates Mic60 levels, we performed chromatin immunoprecipitation and reporter gene analysis. We discovered that VDR directly binds to the Immt 5’ promoter region spanning positions −3157 to −2323 and thereby upregulates Mic60. Our study provides the first demonstration that a reduction in Mic60 levels due to aging may be one of the mechanisms underlying the development of aging-associated NAFLD. In addition, vitamin D3 could positively regulate Mic60 expression, and this may be one of the important mechanisms by which vitamin D could ameliorate age-induced NAFLD.
참고문헌 (53)
- Maurice, J., "Non-alcoholic fatty liver disease", Clin. Med, 18, pp.245~250 (2018)
- Ipsen, D. H., "Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease", Cell Mol. Life Sci, 75, pp.3313~3327 (2018)
- Li, Y., "Non-alcoholic Fatty Liver Disease and Liver Fibrosis during Aging", Aging Dis, 13, pp.1239~1251 (2022)
- Gong, Z., "Hepatic lipid metabolism and non alcoholic fatty liver disease in aging", Mol. Cell Endocrinol, 455, pp.115~130 (2017)
- Barzilai, N., "The critical role of metabolic pathways in aging", Diabetes, 61, pp.1315~1322 (2012)
- Berryman, D. E., "Role of the GH", IGF-1 axis in lifespan and healthspan : lessons from animal models, 2008, pp.18, 455~471
- Kamagate, A., "FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice", J. Clin. Investig, 118, pp.2347~2364 (2008)
- Haussler, M. R., "Molecular mechanisms of vitamin D action", Calcif Tissue Int, 92, pp.77~98 (2013)
- Berridge, M. J., "Vitamin D, reactive oxygen species and calcium signalling in ageing and disease", Philos. Trans. R Soc Lond B Biol. Sci, 371 (2016)[DOI]
- Kennel, K. A., "Vitamin D deficiency in adults : when to test and how to treat", Mayo Clin. Proc, 85, pp.752~757 (2010)
- Eliades, M., "Vitamin D: a new player in non-alcoholic fatty liver disease?", World J. Gastroenterol, 21, pp.1718~1727 (2015)
- Jaruvongvanich, V., "Vitamin D and histologic severity of nonalcoholic fatty liver disease : A systematic review and meta-analysis", Dig Liver Dis, 49, pp.618~622 (2017)
- Sebastian, D., "Mitochondrial dynamics : coupling mito chondrial fitness with healthy aging", Trends Mol. Med, 23, pp.201~215 (2017)
- Wiedemann, N., "Mitochondrial machineries for protein import and assembly", Annu. Rev. Biochem, 86, pp.685~714 (2017)
- Yi, H. S., "The mitochondrial unfolded protein response and mitohormesis: a perspective on metabolic diseases", J. Mol. Endocrinol, 61, pp.R91~R105 (2018)
- Li, R., "Role of mitochondrial quality control in the patho genesis of nonalcoholic fatty liver disease", Aging, 12, pp.6467~6485 (2020)
- Takeichi, Y., "Non-alcoholic fatty liver disease in mice with hepatocyte-specific deletion of mitochondrial fission factor", Diabetologia, 64, pp.2092~2107 (2021)
- Cogliati, S., "Mitochondrial Cristae: Where Beauty Meets Functionality", Trends Biochem. Sci, 41, pp.261~273 (2016)
- Harner, M., "The mitochondrial contact site complex, a determinant of mitochondrial architecture", EMBO J, 30, pp.4356~4370 (2011)
- van der Laan, M., "Mitochondrial contact site and cristae organizing system", Curr. Opin. Cell Biol, 41, pp.33~42 (2016)
- Colina-Tenorio, L., "Shaping the mitochondrial inner membrane in health and disease", J. Intern. Med, 287, pp.645~664 (2020)
- Tsai, P. I., "Phosphorylates MIC60", Mitofilin to Control Structural Plas ticity of Mitochondrial Crista Junctions, 2018, pp.69, 744~756
- Patten, D. A., "OPA1-dependent cristae modulation is essential for cellular adaptation to metabolic demand", EMBO J, 33, pp.2676~2691 (2014)
- Janer, A., "SLC25A46 is required for mitochondrial lipid homeostasis and cristae maintenance and is responsible for Leigh syndrome", EMBO Mol. Med, 8, pp.1019~1038 (2016)
- Jiang, X., "Activation of mitochondrial protease OMA1 by Bax and Bak promotes cytochrome c release during apoptosis", Proc. Natl Acad. Sci. USA, 111, pp.14782~14787 (2014)
- Viana, M. P., "Pro tease OMA1 modulates mitochondrial bioenergetics and ultrastructure through dynamic association with MICOS complex", iScience, 24, pp.102119~ (2021)
- Eramo, M. J., "The ‘mitochondrial contact site and cristae organising system’(MICOS)in health and human disease", J. Biochem, 167, pp.243~255 (2020)
- Keane, J. T., "Vitamin D and the Liver Correlation or Cause?", Nutrients, 10 (2018)[DOI]
- Zhou, L., "Cidea promotes hepatic steatosis by sensing dietary fatty acids", Hepatology, 56, pp.95~107 (2012)
- Bechmann, L. P., "The interaction of hepatic lipid and glucose metabolism in liver diseases", J. Hepatol, 56, pp.952~964 (2012)
- Lee, Y. J., "Monoacylglycerol O-acyltransferase 1(MGAT1)localizes to the ER and lipid droplets promoting triacylglycerol synthesis", BMB Rep, 50, pp.367~372 (2017)
- Janikiewicz, J., "Mitochondria-associated membranes in aging and senes cence : structure, function, and dynamics", Cell Death Dis, 9, pp.332~ (2018)
- Ryan, Z. C., "1alpha, 25-Dihydroxyvitamin D3 Regulates Mitochondrial Oxygen Consumption and Dynamics in Human Skeletal Muscle Cells", J. Biol. Chem, 291, pp.1514~1528 (2016)
- Quiros, P. M., "New roles for mitochondrial proteases in health, ageing and disease", Nat. Rev. Mol. Cell Biol, 16, pp.345~359 (2015)
- Stephan, T., "MICOS assembly controls mitochondrial inner membrane remodeling and crista junction redistribution to mediate cristae formation", EMBO J, 39, pp.e104105~ (2020)
- Karabicici, M., "Doxorubicin-induced senescence promotes stemness and tumorigenicity in EpCAM-", CD133-nonstem cell population in hepatocellular carcinoma cell line, HuH-7, 2021, pp.15, 2185~2202
- Gil, A., "Vitamin D : Classic and Novel Actions", Ann. Nutr. Metab, 72, pp.87~95 (2018)
- Picca, A., "Cell Death and Inflam mation: The Role of Mitochondria in Health and Disease", Cells, 10 (2021)[DOI]
- Luo, Y., "The Significance of Mitochondrial Dysfunction in Cancer", Int. J. Mol. Sci, 21 (2020)[DOI]
- Baseler, W. A., "Proteomic alterations of distinct mitochondrial subpopula tions in the type 1 diabetic heart : contribution of protein import dysfunction", Am. J. Physiol. Regul Integr. Comp. Physiol, 300, pp.R186~R200 (2011)
- Thapa, D., "Transgenic overexpression of mitofilin attenuates diabetes mellitus-associated cardiac and mitochondria dysfunction", J. Mol. Cell Cardiol, 79, pp.212~223 (2015)
- Guarani, V., "QIL1 mutation causes MICOS disassembly and early onset fatal mitochondrial encephalopathy with liver disease", Elife, 5 (2016)[DOI]
- Lamant, M., "ApoO, a novel apolipoprotein, is an original glycoprotein up regulated by diabetes in human heart", J. Biol. Chem, 281, pp.36289~36302 (2006)
- Lee, H. J., "Downregulation of mitochondrial lon protease impairs mito chondrial function and causes hepatic insulin resistance in human liver SK-HEP-1cells", Diabetologia, 54, pp.1437~1446 (2011)
- Sanders, F. W., "De novo lipogenesis in the liver in health and disease : more than just a shunting yard for glucose", Biol. Rev. Camb. Philos. Soc, 91, pp.452~468 (2016)
- Rada, P., "Under standing lipotoxicity in NAFLD pathogenesis : is CD36 a key driver", Cell Death Dis, 11, pp.802~ (2020)
- Chen, Y., "Mitochondrial Metabolic Reprogramming by CD36 Signaling Drives Macrophage Inflammatory Responses", Circ. Res, 125, pp.1087~1102 (2019)
- Tang, J., "Sam50-Mic19-Mic60 axis determines mitochondrial cristae archi tecture by mediating mitochondrial outer and inner membrane contact", Cell Death Differ, 27, pp.146~160 (2020)
- Chen, L., "Loss of Sam50 in hepatocytes induces cardiolipin-dependent mitochondrial membrane remodeling to trigger mtDNA release and liver injury", Hepatology, 76, pp.1389~1408 (2022)
- Li, Z., "The role of SAMM50 in non-alcoholic fatty liver disease : from genetics to mechanisms", FEBS Open Bio, 11, pp.1893~1906 (2021)
- Roth, C. L., "Vitamin D deficiency in obese rats exacerbates nonalcoholic fatty liver disease and increases hepatic resistin and Toll-like receptor activation", Hepatology, 55, pp.1103~1111 (2012)
- Lee, Y. J., "Vitamin D Rescues Pancreatic beta Cell Dysfunction due to Iron Overload via Elevation of the Vitamin D Receptor and Maintenance of Ca(2+)Homeostasis", Mol. Nutr. Food Res, 65, pp.e2000772~ (2021)
- Pines, A., "Vitamin D and health issues-questioned benefits", Climacteric, 17, pp.657~659 (2014)