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Hao L, Li S, Chen G, Hu X. Regulation of UCP2 in nonalcoholic fatty liver disease: From mechanisms to natural product. Chem Biol Drug Des 2024; 103. [DOI: 10.1111/cbdd.14461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 01/09/2024] [Indexed: 01/04/2025]
Abstract
AbstractNonalcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with lipid deposition in liver cells and/or subsequent inflammation, excluding other known causes. NAFLD is a subset of metabolic syndrome that ranges from simple steatohepatitis (NASH), fibrosis to cirrhosis and hepatocellular carcinoma (HCC). At present, the pathogenesis of NAFLD remains unclear. Among the many factors that shape these transitions, uncoupling protein 2 (UCP2) may be involved in every stage of the disease. UCP2 is a carrier protein that responds to fatty acids (FAs) in mitochondrial intima and has a wide tissue distribution. However, the biological function of UCP2 has not been fully elucidated, and most of our current knowledge comes from cell and animal experiments. These data suggest that UCP2 plays a role in lipid metabolism, oxidative stress, apoptosis, and even cancer. In this review, we summarize the structure, distribution, and biological function of UCP2 and its role in the progression of NAFLD, as well as natural products targeting UCP2 to improve NAFLD.
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Affiliation(s)
- Liyuan Hao
- Hospital of Chengdu University of Traditional Chinese Medicine Chengdu China
- Chengdu University of Traditional Chinese Medicine Chengdu China
| | - Shenghao Li
- Hospital of Chengdu University of Traditional Chinese Medicine Chengdu China
- Chengdu University of Traditional Chinese Medicine Chengdu China
| | - Guo Chen
- Hospital of Chengdu University of Traditional Chinese Medicine Chengdu China
| | - Xiaoyu Hu
- Hospital of Chengdu University of Traditional Chinese Medicine Chengdu China
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Ježek P, Holendová B, Garlid KD, Jabůrek M. Mitochondrial Uncoupling Proteins: Subtle Regulators of Cellular Redox Signaling. Antioxid Redox Signal 2018; 29:667-714. [PMID: 29351723 PMCID: PMC6071544 DOI: 10.1089/ars.2017.7225] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
SIGNIFICANCE Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δp or its potential component, ΔΨ, which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1-5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δp dissipation decreases superoxide formation dependent on Δp. UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. CRITICAL ISSUES A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg2+, or increased pyruvate accumulation may initiate UCP-mediated redox signaling. FUTURE DIRECTIONS Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667-714.
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Affiliation(s)
- Petr Ježek
- 1 Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences , Prague, Czech Republic
| | - Blanka Holendová
- 1 Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences , Prague, Czech Republic
| | - Keith D Garlid
- 2 UCLA Cardiovascular Research Laboratory, David Geffen School of Medicine at UCLA , Los Angeles, California
| | - Martin Jabůrek
- 1 Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences , Prague, Czech Republic
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Pan P, Wang X, Liu D. The potential mechanism of mitochondrial dysfunction in septic cardiomyopathy. J Int Med Res 2018; 46:2157-2169. [PMID: 29637807 PMCID: PMC6023059 DOI: 10.1177/0300060518765896] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Septic cardiomyopathy is one of the most serious complications of sepsis or septic shock. Basic and clinical research has studied the mechanism of cardiac dysfunction for more than five decades. It has become clear that myocardial depression is not related to hypoperfusion. As the heart is highly dependent on abundant adenosine triphosphate (ATP) levels to maintain its contraction and diastolic function, impaired mitochondrial function is lethally detrimental to the heart. Research has shown that mitochondria play an important role in organ damage during sepsis. The mitochondria-related mechanisms in septic cardiomyopathy have been discussed in terms of restoring mitochondrial function. Mitochondrial uncoupling proteins located in the mitochondrial inner membrane can promote proton leakage across the mitochondrial inner membrane. Recent studies have demonstrated that proton leakage is the essential regulator of mitochondrial membrane potential and the generation of reactive oxygen species (ROS) and ATP. Other mechanisms involved in septic cardiomyopathy include mitochondrial ROS production and oxidative stress, mitochondria Ca2+ handling, mitochondrial DNA in sepsis, mitochondrial fission and fusion, mitochondrial biogenesis, mitochondrial gene regulation and mitochondria autophagy. This review will provide an overview of recent insights into the factors contributing to septic cardiomyopathy.
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Affiliation(s)
- Pan Pan
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaoting Wang
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
| | - Dawei Liu
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China
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Marques D, Ferreira-Costa LR, Ferreira-Costa LL, Correa RDS, Borges AMP, Ito FR, Ramos CCDO, Bortolin RH, Luchessi AD, Ribeiro-dos-Santos Â, Santos S, Silbiger VN. Association of insertion-deletions polymorphisms with colorectal cancer risk and clinical features. World J Gastroenterol 2017; 23:6854-6867. [PMID: 29085228 PMCID: PMC5645618 DOI: 10.3748/wjg.v23.i37.6854] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 06/24/2017] [Accepted: 08/15/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the association between 16 insertion-deletions (INDEL) polymorphisms, colorectal cancer (CRC) risk and clinical features in an admixed population.
METHODS One hundred and forty patients with CRC and 140 cancer-free subjects were examined. Genomic DNA was extracted from peripheral blood samples. Polymorphisms and genomic ancestry distribution were assayed by Multiplex-PCR reaction, separated by capillary electrophoresis on the ABI 3130 Genetic Analyzer instrument and analyzed on GeneMapper ID v3.2. Clinicopathological data were obtained by consulting the patients’ clinical charts, intra-operative documentation, and pathology scoring.
RESULTS Logistic regression analysis showed that polymorphism variations in IL4 gene was associated with increased CRC risk, while TYMS and UCP2 genes were associated with decreased risk. Reference to anatomical localization of tumor Del allele of NFKB1 and CASP8 were associated with more colon related incidents than rectosigmoid. In relation to the INDEL association with tumor node metastasis (TNM) stage risk, the Ins alleles of ACE, HLAG and TP53 (6 bp INDEL) were associated with higher TNM stage. Furthermore, regarding INDEL association with relapse risk, the Ins alleles of ACE, HLAG, and UGT1A1 were associated with early relapse risk, as well as the Del allele of TYMS. Regarding INDEL association with death risk before 10 years, the Ins allele of SGSM3 and UGT1A1 were associated with death risk.
CONCLUSION The INDEL variations in ACE, UCP2, TYMS, IL4, NFKB1, CASP8, TP53, HLAG, UGT1A1, and SGSM3 were associated with CRC risk and clinical features in an admixed population. These data suggest that this cancer panel might be useful as a complementary tool for better clinical management, and more studies need to be conducted to confirm these findings.
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Affiliation(s)
- Diego Marques
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Programa de Pós-graduação em Ciências Farmacêutica, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém 66055-080, Pará, Brazil
| | - Layse Raynara Ferreira-Costa
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
| | - Lorenna Larissa Ferreira-Costa
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
| | - Romualdo da Silva Correa
- Departamento de Cirurgia Oncológica, Liga Norte Riograndense Contra o Câncer, Natal 59040-000, Rio Grande do Norte, Brazil
| | - Aline Maciel Pinheiro Borges
- Departamento de Cirurgia Oncológica, Liga Norte Riograndense Contra o Câncer, Natal 59040-000, Rio Grande do Norte, Brazil
| | - Fernanda Ribeiro Ito
- Departamento de Cirurgia Oncológica, Liga Norte Riograndense Contra o Câncer, Natal 59040-000, Rio Grande do Norte, Brazil
| | - Carlos Cesar de Oliveira Ramos
- Laboratório de Patologia e Citopatologia, Liga Norte Riograndense Contra o Câncer, Natal 59040-000, Rio Grande do Norte, Brazil
| | - Raul Hernandes Bortolin
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Programa de Pós-graduação em Ciências Farmacêutica, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
| | - André Ducati Luchessi
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Programa de Pós-graduação em Ciências Farmacêutica, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
| | - Ândrea Ribeiro-dos-Santos
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém 66055-080, Pará, Brazil
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém 66073-005, Pará, Brazil
| | - Sidney Santos
- Laboratório de Genética Humana e Médica, Universidade Federal do Pará, Belém 66055-080, Pará, Brazil
- Núcleo de Pesquisas em Oncologia, Universidade Federal do Pará, Belém 66073-005, Pará, Brazil
| | - Vivian Nogueira Silbiger
- Laboratório de Bioanálise e Biotecnologia Molecular, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Departamento de Análises Clínicas e Toxicológicas, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
- Programa de Pós-graduação em Ciências Farmacêutica, Universidade Federal do Rio Grande do Norte, Natal 59012-570, Rio Grande do Norte, Brazil
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Lee YYL, Zhou Y, Jelinek HF, Hambly BD, McLachlan CS. The association of uncoupling protein 2 (UCP2) exon 8 insertion/deletion polymorphism and ECG derived QRS duration: A cross-sectional study in an Australian rural population. Int J Cardiol 2016; 228:507-510. [PMID: 27875726 DOI: 10.1016/j.ijcard.2016.11.100] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Accepted: 11/06/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Associations between inherited mitochondrial disease and cardiac conduction have been previously described. However, there are no available studies exploring the mitochondrial uncoupling protein 2 gene (UCP2) insertion/deletion (I/D) polymorphisms interaction on cardiac electrical conduction. Our aim was to determine if ECG-derived QRS duration is associated with UCP2 DD genotype in a cross-sectional Australian aging rural population. METHODS A retrospective study design utilizing a rural health diabetic screening clinic data-base containing observational data from September 2011 to September 2014. Inclusion criteria included were having ECG parameters such as QRS duration measures and a DNA sample within the same subject. Genomic DNA was extracted and subjects were genotyped for the 45-bp I/D polymorphism in the 3'-untranslated region of UCP2. RESULTS 281 individuals were available for analysis. On the basis of QRS duration >140ms we found an increased percentage of our population with DD homozygotes, compared to ID heterozygotes and II homozygotes (p=0.047). For other ECG parameters; mean PQ duration, QTc across UCP2 genotypes was not significant (p=NS). QTc using a cut-off >440ms in contingency table analysis revealed no significant differences across UCP2 I/D genotypes. Mean QT dispersion (QTd) was paradoxically less in the UCP2 DD genotype compared to UCP2 II subgroup (p=0.034). DISCUSSION We have demonstrated an association between increasing ECG-derived QRS duration >140ms and the UCP2 DD polymorphism. The lack of association with ECG derived QTd and UCP2 DD may suggest that gene-related QRS duration prolongation is independent of cardiac hypertrophy.
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Affiliation(s)
- Yvonne Yin Leng Lee
- Rural Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Yuling Zhou
- Rural Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia
| | - Herbert F Jelinek
- Australia School of Health Sciences, Charles Stuart University, Albury, Australia
| | - Brett D Hambly
- Discipline of Pathology, Sydney Medical School, University of Sydney, Australia
| | - Craig S McLachlan
- Rural Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.
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Zhou Y, Ning Z, Lee Y, Hambly BD, McLachlan CS. Shortened leukocyte telomere length in type 2 diabetes mellitus: genetic polymorphisms in mitochondrial uncoupling proteins and telomeric pathways. Clin Transl Med 2016; 5:8. [PMID: 26951191 PMCID: PMC4781821 DOI: 10.1186/s40169-016-0089-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 02/29/2016] [Indexed: 12/17/2022] Open
Abstract
Current debate in type 2 diabetes (T2DM) has focused on shortened leukocyte telomere length (LTL) as the result of a number of possible causes, including polymorphisms in mitochondrial uncoupling proteins (UCPs) leading to oxidative stress, telomere regulatory pathway gene polymorphisms, or as a direct result of associated cardiovascular complications inducing tissue organ inflammation and oxidative stress. There is evidence that a heritable shorter telomere trait is a risk factor for development of T2DM. This review discusses the contribution and balance of genetic regulation of UCPs and telomere pathways in the context of T2DM. We discuss genotypes that are well known to influence the shortening of LTL, in particular OBFC1 and telomerase genotypes such as TERC. Interestingly, the interaction between short telomeres and T2DM risk appears to involve mitochondrial dysfunction as an intermediate process. A hypothesis is presented that genetic heterogeneity within UCPs may directly affect oxidative stress that feeds back to influence the fine balance of telomere regulation, cell cycle regulation and diabetes risk and/or metabolic disease progression.
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Affiliation(s)
- Yuling Zhou
- Faculty of Medicine, Rural Clinical School, University of New South Wales, Samuels Building, Level 3, Room 327, Sydney, 2052, Australia.
| | - Zhixin Ning
- Faculty of Medicine, Rural Clinical School, University of New South Wales, Samuels Building, Level 3, Room 327, Sydney, 2052, Australia.
| | - Yvonne Lee
- Faculty of Medicine, Rural Clinical School, University of New South Wales, Samuels Building, Level 3, Room 327, Sydney, 2052, Australia.
| | - Brett D Hambly
- Discipline of Pathology, Bosch Institute, Sydney Medical School, University of Sydney, Sydney, Australia.
| | - Craig S McLachlan
- Faculty of Medicine, Rural Clinical School, University of New South Wales, Samuels Building, Level 3, Room 327, Sydney, 2052, Australia.
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Henry RR, Chilton R, Garvey WT. New options for the treatment of obesity and type 2 diabetes mellitus (narrative review). J Diabetes Complications 2013; 27:508-18. [PMID: 23726071 PMCID: PMC4139280 DOI: 10.1016/j.jdiacomp.2013.04.011] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2013] [Revised: 04/19/2013] [Accepted: 04/22/2013] [Indexed: 12/15/2022]
Abstract
Moderate weight loss (>5%), which has been associated with improvements in glycemic parameters in patients with dysglycemia, also reduces the presence of other comorbidities, including dyslipidemia and hypertension, culminating in a reduced risk of cardiovascular disease. Lifestyle changes are the recommended preliminary approach to weight loss, with an initial weight-loss goal of 10% of body weight achieved over 6 months at a rate of 1-2 pounds per week selected as an appropriate target to decrease the severity of obesity-related risk factors. Implementing and maintaining the lifestyle changes associated with weight loss can, however, be challenging for many patients. Therefore, additional interventions sometimes may be necessary. Bariatric surgery can also be a highly effective option for weight loss and comorbidity reduction, but surgery carries considerable risks and is still applicable only to selected patients with type 2 diabetes. Thus, attention is turning to the use of weight-loss medications, including 2 recently approved compounds: twice-daily lorcaserin and a once-daily combination of phentermine and topiramate extended-release, both shown to be safe and effective therapies in the management of obesity in patients with type 2 diabetes.
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Affiliation(s)
- Robert R Henry
- Center for Metabolic Research, VA San Diego Healthcare System and University of California San Diego, San Diego, CA, USA.
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Shin SS, Yoon M. The herbal composition GGEx18 from Laminaria japonica, Rheum palmatum, and Ephedra sinica inhibits high-fat diet-induced hepatic steatosis via hepatic PPARα activation. PHARMACEUTICAL BIOLOGY 2012; 50:1261-1268. [PMID: 22870903 DOI: 10.3109/13880209.2012.666982] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
CONTEXT The activation of peroxisome proliferator-activated receptor α (PPARα) target genes promotes hepatic oxidation of fatty acids. We hypothesized that Gyeongshingangjeehwan 18 (GGEx18), a mixture of three herbs, Laminaria japonica Aresch (Laminariaceae), Rheum palmatum L. (Polygonaceae), and Ephedra sinica Stapf (Ephedraceae), can regulate high-fat diet-induced hepatic steatosis through PPARα activation in the liver. OBJECTIVE To investigate the effects of GGEx18 on obesity-related hepatic steatosis and the responsible mechanism. MATERIALS AND METHODS The effects of GGEx18 on hepatic lipid accumulation, serum lipid profiles, and the expression of PPARα target genes were studied in high-fat diet-induced obese mice. The effects of GGEx18 on the expression of the PPARα targets and PPARα reporter gene activation were measured in NMu2Li liver cells. RESULTS GGEx18 administration to obese mice for 9 weeks markedly (p<0.05) decreased hepatic lipid accumulation compared with that in obese control mice. Serum triglyceride and total cholesterol levels were significantly (p <0.05) decreased by GGEx18. GGEx18 treatment increased the messenger RNA levels of PPARα target genes, which are responsible for fatty acid oxidation, in liver tissues. Consistent with the in vivo data, similar activation of genes was observed in GGEx18-treated NMu2Li liver cells. GGEx18 also elevated PPARα reporter gene expression in NMu2Li cells. DISCUSSION AND CONCLUSION These results suggest that GGEx18 prevents hepatic steatosis and hyperlipidemia in high-fat diet-induced obese mice, and this process may be mediated through PPARα activation in the liver.
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Affiliation(s)
- Soon Shik Shin
- Department of Formula Sciences, College of Oriental Medicine, Dongeui University, Busan, Korea
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Tranah GJ. Mitochondrial-nuclear epistasis: implications for human aging and longevity. Ageing Res Rev 2011; 10:238-52. [PMID: 20601194 DOI: 10.1016/j.arr.2010.06.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2010] [Revised: 06/17/2010] [Accepted: 06/17/2010] [Indexed: 12/22/2022]
Abstract
There is substantial evidence that mitochondria are involved in the aging process. Mitochondrial function requires the coordinated expression of hundreds of nuclear genes and a few dozen mitochondrial genes, many of which have been associated with either extended or shortened life span. Impaired mitochondrial function resulting from mtDNA and nuclear DNA variation is likely to contribute to an imbalance in cellular energy homeostasis, increased vulnerability to oxidative stress, and an increased rate of cellular senescence and aging. The complex genetic architecture of mitochondria suggests that there may be an equally complex set of gene interactions (epistases) involving genetic variation in the nuclear and mitochondrial genomes. Results from Drosophila suggest that the effects of mtDNA haplotypes on longevity vary among different nuclear allelic backgrounds, which could account for the inconsistent associations that have been observed between mitochondrial DNA (mtDNA) haplogroups and survival in humans. A diversity of pathways may influence the way mitochondria and nuclear-mitochondrial interactions modulate longevity, including: oxidative phosphorylation; mitochondrial uncoupling; antioxidant defenses; mitochondrial fission and fusion; and sirtuin regulation of mitochondrial genes. We hypothesize that aging and longevity, as complex traits having a significant genetic component, are likely to be controlled by nuclear gene variants interacting with both inherited and somatic mtDNA variability.
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Wang J, Liu C, Zhao H, Wang F, Guo J, Xie H, Lu X, Bao Y, Pei L, Niu B, Zhong R, Zheng X, Zhang T. Association between a 45-bp 3'untranslated insertion/deletion polymorphism in exon 8 of UCP2 gene and neural tube defects in a high-risk area of China. Reprod Sci 2011; 18:556-60. [PMID: 21266666 DOI: 10.1177/1933719110393026] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Uncoupling protein 2(UCP2) is an attractive candidate gene for screening neural tube defects (NTDs) risk. In this study, polymerase chain reaction and agarose gel electrophoresis were used to determine the distribution of the polymorphism in a case group of 140 deliveries with NTDs, and a control group of 251 normal newborns. We found that the frequencies of allele I and genotypes ID + II were higher in the case group than in the control group (P = .167, OR = 1.4, 95% CI, 0.9-2.1; P = .132, OR = 1.44, 95% CI, 0.89-2.33, respectively); and at low maternal educational level, the frequency of ID + II genotypes was significantly higher in the NTD case group (P < .05, OR = 1.7, 95% CI, 1.01-2.79). The result suggested that the polymorphism in UCP2 may be a potential genetic risk factor for NTDs in a high-risk area of China, and the association was influenced by maternal education.
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Mitchell A, Pangilinan F, Van der Meer J, Molloy AM, Troendle J, Conley M, Kirke PN, Scott JM, Brody LC, Mills JL. Uncoupling protein 2 polymorphisms as risk factors for NTDs. ACTA ACUST UNITED AC 2009; 85:156-60. [PMID: 19137581 DOI: 10.1002/bdra.20520] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Both environmental and genetic factors are involved in the etiology of NTDs. Inadequate folate intake and obesity are important environmental risk factors. Several folate-related genetic variants have been identified as risk factors; however, little is known about how genetic variants relate to the increased risk seen in obese women. Uncoupling Protein 2 (UCP2) is an attractive candidate to screen for NTD risk because of its possible role in obesity as well as energy metabolism, type-2 diabetes, and the regulation of reactive oxygen species. Interestingly, a previous study found that a common UCP2 compound homozygous genotype was associated with a threefold increase in NTD risk. METHODS We evaluated three polymorphisms, -866G>A, A55V, and the 3'UTR 45 bp insertion/deletion, as risk factors for NTDs in Irish NTD cases (n = 169), their mothers (n = 163), their fathers (n = 167), and normal control subjects (n = 332). RESULTS Allele and genotype frequencies were not significantly different when comparing NTD mothers, NTD fathers, or affected children to controls. Additionally, the previously reported risk genotype (combined homozygosity of 55VV and 3'UTR 45 bp deletion/deletion) was not present at a higher frequency in any NTD group when compared to controls. CONCLUSIONS In our Irish study population, UCP2 polymorphisms did not influence NTD risk. Moreover, the prevalence of this allele in other populations was similar to the Irish prevalence but far lower than reported in the previous NTD study, suggesting that this previous finding of an association with NTDs might have been due to an unrepresentative study sample.
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Affiliation(s)
- Adam Mitchell
- Molecular Pathogenesis Section, Genome Technology Branch, National Human Genome Research Institute, 50 South Drive, Bethesda, MD 20892-8004, USA
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Ramsay TG, Mitchell AD, Richards MP. Uncoupling protein expression in skeletal muscle and adipose tissue in response to in vivo porcine somatotropin treatment. Domest Anim Endocrinol 2008; 35:130-41. [PMID: 18638661 DOI: 10.1016/j.domaniend.2007.12.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2006] [Revised: 11/08/2007] [Accepted: 12/05/2007] [Indexed: 11/25/2022]
Abstract
These experiments examined the potential roles of somatropin (pST) and IGF-I in the regulation of uncoupling protein (UCP)2 and UCP3 and their regulatory proteins peroxisome proliferator activated receptor (PPAR) alpha, gamma and delta using in vivo pST treatment of swine and in vitro supplementation of pST or IGF-I to adipose slices. Six, 90kg barrows were treated with recombinant pST (10mg) for 2 week while another six pigs were injected with buffer. Total RNA from outer subcutaneous adipose (OSQ) and middle subcutaneous adipose (MSQ) tissues, leaf fat, liver and longissimus (LM) was amplified by reverse transcription-PCR with quantification of transcripts by capillary electrophoresis with laser-induced fluorescence detection. UCP2 mRNA abundance increased in liver (P<0.001) and all three adipose tissues by pST treatment (P<0.05). Administration of pST increased UCP3 mRNA abundance by 42% in LM (P<0.01). PPARalpha mRNA abundance increased with pST treatment by 29% in liver (P<0.05), while decreasing 25% in LM (P<0.05). PPARgamma mRNA abundance decreased 32% (P<0.01) while PPARdelta increased 48% in LM (P<0.01) with pST administration. In vitro, pST reduced UCP2 mRNA abundance in OSQ and MSQ tissue slices (P<0.05). UCP3 mRNA abundance decreased in OSQ (P<0.05) but increased in MSQ (P<0.05) with pST. In contrast, IGF-I increased UCP2 and UCP3 mRNA abundance in both MSQ and OSQ slices (P<0.05). These experiments suggest pST, IGF-I and metabolic adaptations to pST contribute to regulating UCP2 and UCP3.
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Affiliation(s)
- T G Ramsay
- Growth Biology Laboratory, U.S. Department of Agriculture-Agricultural Research Service, Beltsville, MD 20705, USA.
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Ramsay T, Mitchell A. Impact of dietary protein content on uncoupling protein mRNA abundance in swine. Comp Biochem Physiol B Biochem Mol Biol 2008; 149:562-71. [DOI: 10.1016/j.cbpb.2007.11.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2007] [Revised: 11/08/2007] [Accepted: 11/08/2007] [Indexed: 11/26/2022]
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Schrauwen P, Hesselink M. Uncoupling protein 3 and physical activity: the role of uncoupling protein 3 in energy metabolism revisited. Proc Nutr Soc 2007; 62:635-43. [PMID: 14692599 DOI: 10.1079/pns2003277] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Physical activity influences energy metabolism in human subjects by increasing activity-induced energy expenditure and resting metabolic rate for several hours after exercise. On the other hand, physical activity increases mechanical energy efficiency, suggesting that trained subjects would need less energy for daily activities. The underlying mechanism by which physical activity influences energy metabolism is largely unknown. The skeletal muscle-specific homologue of uncoupling protein (UCP) 1, UCP3, could possibly play a major role in energy expenditure. UCP3 is, like UCP1, able to uncouple respiration from ATP production. A strong link or association between theUCP3gene and energy metabolism was found. Furthermore, UCP3 mRNA expression is related to sleeping metabolic rate, and thyroid hormone, a powerful stimulator of energy expenditure, up regulates UCP3. Finally, mice overexpressing UCP3 are hyperphagic but lean. These findings indicated that UCP3 is related to energy metabolism and that UCP3 could have a role in the effect of physical activity on energy expenditure. Thus, acute exercise up regulates UCP3, whereas endurance training results in the down-regulation of UCP3 protein content. Only a minimal amount of physical activity is needed for down-regulation of UCP3. Moreover, there is very strong evidence that UCP3 is negatively related to mechanical energy efficiency, suggesting that the down-regulation of UCP3 with training increases mechanical energy efficiency. Taken together, although the exact function of UCP3 is still unknown, exercise and training studies clearly show that under certain circumstances UCP3 is strongly related to human energy metabolism, possibly as a secondary effect of its (yet) unknown primary function.
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Affiliation(s)
- Patrick Schrauwen
- Nutrition and Toxicology Research Institute Maastricht, Department of Human Biology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands.
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16
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Oh KS, Kim M, Lee J, Kim MJ, Nam YS, Ham JE, Shin SS, Lee CM, Yoon M. Liver PPARα and UCP2 are involved in the regulation of obesity and lipid metabolism by swim training in genetically obese db/db mice. Biochem Biophys Res Commun 2006; 345:1232-9. [PMID: 16716264 DOI: 10.1016/j.bbrc.2006.04.182] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2006] [Accepted: 04/29/2006] [Indexed: 11/21/2022]
Abstract
Swim training for 6 weeks significantly decreased body weight gain, adipose tissue mass, and adipocyte size in both sexes of genetically obese db/db mice compared with their respective sedentary controls. Swim training also caused significant decreases in serum levels of free fatty acids, triglycerides, and total cholesterol in both sexes of obese mice. Concomitantly, hepatic mRNA levels of peroxisome proliferator-activated receptor alpha (PPARalpha) target enzymes responsible for mitochondrial and peroxisomal fatty acid beta-oxidation were significantly increased by swim training. Moreover, mRNA levels of uncoupling protein 2 (UCP2) in liver were also markedly increased by swim training. In conclusion, these results suggest that swim training-induced transcriptional activation of hepatic PPARalpha target enzymes and UCP2 may effectively prevent body weight gain, adiposity, and lipid disorders caused by leptin receptor deficiency in both sexes of mice.
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Affiliation(s)
- Ki Sook Oh
- Department of Physical Education, Sookmyung Women's University, Seoul 140-742, Republic of Korea
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17
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Boschini RP, Garcia Júnior JR. Regulação da expressão gênica das UCP2 e UCP3 pela restrição energética,jejum e exercício físico. REV NUTR 2005. [DOI: 10.1590/s1415-52732005000600006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
O tecido adiposo marrom, onde se localiza a proteína desacopladora 1 (UCP1 - uncoupling protein 1), é um tecido termogênico presente somente nos pequenos mamíferos e neonatos, com função de manter temperatura e peso corporal estáveis quando da exposição ao frio ou consumo de dietas hipercalóricas. Como a UCP1 está localizada exclusivamente no tecido adiposo marrom, tecido pouco expressado em adultos, os estudos dão ênfase às proteínas desacopladoras 2 e 3 (UCP2 e UCP3), proteínas homólogas à UCP1, expressas em múltiplos tecidos e nos músculos esqueléticos, respectivamente. A atividade física provoca aumento do RNAm da UCP2 e UCP3, questiona-se, porém, se este aumento é devido a mudanças no metabolismo de gordura ou a mudanças no metabolismo energético. Durante a restrição energética ou jejum, há depleção de gordura corporal e aumento da concentração plasmática de ácidos graxos livres, com regulação positiva da UCP2 e da UCP3 no músculo e aumento da oxidação lipídica. A concentração elevada de ácidos graxos representa sinal intracelular importante na indução da expressão das UCP no músculo, o que pode estar ligado à sua utilização como combustível até que ocorra aumento da demanda do organismo para dissipação da energia. No entanto, discute-se se a UCP2 e a UCP3 no músculo esquelético têm como função mediar a termogênese ou regular a oxidação de lipídios.
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18
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Slattery ML, Murtaugh MA, Sweeney C, Ma KN, Potter JD, Caan BJ, Samowitz W. PPARgamma, energy balance, and associations with colon and rectal cancer. Nutr Cancer 2005; 51:155-61. [PMID: 15860437 DOI: 10.1207/s15327914nc5102_5] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Peroxisome proliferator-activated receptor-gamma (PPARgamma) has been hypothesized as being involved in colorectal cancer given its role in adipocyte development and insulin resistance. In this study we evaluated the association between the Pro12Ala (P12A) PPARgamma polymorphism and body mass index (BMI), waist-to-hip ratio (WHR), physical activity level, and energy intake and risk of colorectal cancer using data from a population-based, case-control study of colon cancer (1,577 cases and 1,971 controls) and rectal cancer (794 cases and 1,001 controls). We further evaluated how the P12A PPARgamma polymorphism is associated with obesity and fat pattern in the control population. The odd ratio for PPARgamma PA or AA genotype relative to the PP genotype for colon cancer was 0.9 (95% confidence interval, CI=0.8-1.0) and for rectal cancer was 1.2 (95% CI=1.0-1.5) adjusting for race, age, and sex. P12A PPARgamma did not significantly interact with BMI, WHR, energy intake, and energy expenditure to alter risk of colon or rectal cancer. Furthermore, the P12A PPARgamma polymorphism was not associated with obesity or WHR in the control population; it did not interact with energy intake or energy expenditure to alter risk of obesity or large WHR. These data do not support the hypothesis that the P12A PPARgamma polymorphism is associated with colon or rectal cancer through regulation of energy balance.
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Affiliation(s)
- Martha L Slattery
- Health Research Center, University of Utah, Salt Lake City 84108, USA.
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19
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Turkish AR, Henneberry AL, Cromley D, Padamsee M, Oelkers P, Bazzi H, Christiano AM, Billheimer JT, Sturley SL. Identification of two novel human acyl-CoA wax alcohol acyltransferases: members of the diacylglycerol acyltransferase 2 (DGAT2) gene superfamily. J Biol Chem 2005; 280:14755-64. [PMID: 15671038 DOI: 10.1074/jbc.m500025200] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The esterification of alcohols such as sterols, diacylglycerols, and monoacylglycerols with fatty acids represents the formation of both storage and cytoprotective molecules. Conversely, the overproduction of these molecules is associated with several disease pathologies, including atherosclerosis and obesity. The human acyl-CoA:diacylglycerol acyltransferase (DGAT) 2 gene superfamily comprises seven members, four of which have been previously implicated in the synthesis of di- or triacylglycerol. The remaining 3 members comprise an X-linked locus and have not been characterized. We describe here the expression of DGAT2 and the three X-linked genes in Saccharomyces cerevisiae strains virtually devoid of neutral lipids. All four gene products mediate the synthesis of triacylglycerol; however, two of the X-linked genes act as acyl-CoA wax alcohol acyltransferases (AWAT 1 and 2) that predominantly esterify long chain (wax) alcohols with acyl-CoA-derived fatty acids to produce wax esters. AWAT1 and AWAT2 have very distinct substrate preferences in terms of alcohol chain length and fatty acyl saturation. The enzymes are expressed in many human tissues but predominate in skin. In situ hybridizations demonstrate a differentiation-specific expression pattern within the human sebaceous gland for the two AWAT genes, consistent with a significant role in the composition of sebum.
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Affiliation(s)
- Aaron R Turkish
- Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA
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20
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Volcik KA, Shaw GM, Zhu H, Lammer EJ, Finnell RH. Risk factors for neural tube defects: associations between uncoupling protein 2 polymorphisms and spina bifida. BIRTH DEFECTS RESEARCH. PART A, CLINICAL AND MOLECULAR TERATOLOGY 2003; 67:158-61. [PMID: 12797456 DOI: 10.1002/bdra.10019] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Polymorphisms in the mitochondrial membrane transporter gene UCP2 are capable of affecting energy metabolism, body weight regulation, and possibly preventing the buildup of reactive oxygen species, all factors that could contribute to neural tube defect risk through maternal obesity and diabetes. METHODS Genomic DNA was extracted from newborn screening blood spots obtained from infants with spina bifida and nonmalformed control infants. Genotype frequencies of two genetic variants in the UCP2 gene, an amino acid substitution of valine for alanine at codon 55 in exon 4, and a 45-base pair insertion/deletion in the 3' untranslated region of exon 8,were determined by restriction enzyme digestion of PCR amplification products. RESULTS We found the frequency of the 3' untranslated region deletion homozygous genotype (256/256) as well as the A55V homozygous (Val/Val) genotype to be higher in SB infants than in controls (odds ratio [OR], 3.1; 95% confidence interval [CI], 0.9-10.4 and OR = 2.0; 95% CI = 0.3-11.1, respectively). Additionally, the frequency of the combined homozygous 256/256,+ / + genotype was higher in cases and resulted in more than a threefold higher spina bifida risk (OR = 3.6; 95% CI = 1.0-13.1). CONCLUSIONS These data are the first to suggest that polymorphisms in the UCP2 gene may be genetic risk factors of spina bifida.
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Affiliation(s)
- Kelly A Volcik
- Institute of Bioscience and Technology, Texas A&M University System Health Science Center, Houston, Texas 77030-3303, USA
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21
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Abstract
SUMMARY
The uncoupling protein-1 (UCP1) homologues UCP2 and UCP3 are able to uncouple ATP production from mitochondrial respiration, thereby dissipating energy as heat and affecting energy metabolism efficiency. In contrast to UCP1, which plays an important role in adaptive thermogenesis, UCP2 and UCP3 do not have a primary role in the regulation of energy metabolism. UCP2, which is expressed in a wide variety of tissues, including white adipose tissue,skeletal muscle and tissues of the immune system, has been suggested to affect the production of reactive oxygen species. UCP2 has also been suggested to regulate the [ATP]/[ADP] ratio and was recently shown to influence insulin secretion in the β-cells of the pancreas. UCP3, in contrast, is expressed predominantly in skeletal muscle and has been associated with whole-body energy metabolism. However, the primary function of UCP3 is not the regulation of energy metabolism. For example, fasting, a condition attenuating energy expenditure, upregulates UCP3 expression. Moreover, UCP3-knockout mice have a normal metabolic rate. The exact function of UCP3 therefore remains to be elucidated, but putative roles for UCP3 include involvement in the regulation of ROS, in mitochondrial fatty acid transport and in the regulation of glucose metabolism in skeletal muscle. Whatever the primary function of these novel uncoupling proteins, a secondary effect via uncoupling might allow them to influence (but not to regulate) energy metabolism, which would be consistent with the observations from linkage and association studies. Therefore, UCP2 and UCP3 remain interesting targets for pharmacological upregulation in the treatment of obesity and diabetes.
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Affiliation(s)
- Patrick Schrauwen
- Nutrition and Toxicology Research Institute Maastricht (NUTRIM) Department of Human Biology, Maastricht University, The Netherlands.
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22
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Jakus PB, Sipos K, Kispal G, Sandor A. Opposite regulation of uncoupling protein 1 and uncoupling protein 3 in vivo in brown adipose tissue of cold-exposed rats. FEBS Lett 2002; 519:210-4. [PMID: 12023047 DOI: 10.1016/s0014-5793(02)02707-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Earlier we reported a 14-fold increase of glycogen in the brown adipose tissue (BAT) in rats when the animals were placed back from cold to neutral temperature. To elucidate the mechanism, here we compared the level of glucose transporter 4 (GLUT4) protein, uncoupling protein (UCP) 1 and UCP3 mRNA and protein expressions in the BAT under the same conditions. We found that the increased GLUT4 level in cold was maintained during the reacclimation. After 1 week cold exposure the mRNA and protein content of UCP1 increased parallel, while the protein level of UCP3 decreased, contrary to its own mRNA level.
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Affiliation(s)
- P B Jakus
- Department of Biochemistry, Faculty of Medicine, University of Pecs, Szigeti ut 12, Pecs, Hungary
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23
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Clapham JC, Coulthard VH, Moore GB. Concordant mRNA expression of UCP-3, but not UCP-2, with mitochondrial thioesterase-1 in brown adipose tissue and skeletal muscle in db/db diabetic mice. Biochem Biophys Res Commun 2001; 287:1058-62. [PMID: 11587528 DOI: 10.1006/bbrc.2001.5698] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
A recent hypothesis concerning the function of uncoupling protein-3 (UCP-3) depends upon a positive relationship with mitochondrial thioesterase (MTE-1) in situations where fatty acid beta-oxidation is increased. MTE-1 mRNA levels are raised in transgenic mice overexpressing UCP-3 in skeletal muscle and we sought to extend these findings by quantifying in vivo expression of endogenous MTE-1, UCP-1, UCP-2, and UCP-3 mRNA levels in white adipose tissue, interscapular brown adipose tissue, and skeletal muscle in db/db mice. In this study we show that changes in MTE-1 mRNA levels as a result of differences between db/db vs db/+ mice or following long-term treatment of db/db mice with rosiglitazone or Wy-14,643 were more closely correlated with changes in UCP-3 than either UCP-1 or UCP-2 mRNA levels in the tissues examined. The present data contribute to the argument that UCP-3 and MTE-1 are linked within the same metabolic pathway either in response to, or as regulators of, fatty acid beta-oxidation.
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Affiliation(s)
- J C Clapham
- Department of Vascular Biology, GlaxoSmithKline, Harlow, Essex, CM19 5AW, United Kingdom
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24
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Skulachev VP. Mitochondrial physiology and pathology; concepts of programmed death of organelles, cells and organisms. Mol Aspects Med 1999; 20:139-84. [PMID: 10626278 DOI: 10.1016/s0098-2997(99)00008-4] [Citation(s) in RCA: 202] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The review summarizes the present state of our knowledge concerning alternative functions of mitochondria, namely energy conservation in forms of protonic potential and ATP, thermoregulatory energy dissipation as heat, production of useful substances, decomposition of harmful substances, control of cellular processes. The recent progress in understanding of some mitochondrion-linked pathologies is described. The role of reactive oxygen species in these processes is stressed. Possible mechanisms of programmed death of mitochondrion (mitoptosis), cell (apoptosis) and organism (phenoptosis) are considered. A concept is put forward assuming that mitoptosis is involved in some types of apoptosis whereas apoptosis can be a part of a phenoptotic cascade. It is hypothesized that septic shock, as well as the stress-induced brain and heart ischemic diseases and cancer, exemplify mechanisms of phenoptosis purifying population, community of organisms or kin from dangerous or useless individuals.
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Affiliation(s)
- V P Skulachev
- Department of Bioenergetics, A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Russian Federation.
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