Study of Diet Composition, Insulin, Thyroid Hormone Levels and Citrate Carrier Protein Permeability in Obesity
Obesity is a chronic disease of multifactorial origin, characterized by an excessive accumulation of fat that generates multiple metabolic disorders leading to cardiovascular diseases, diabetes mellitus type 2, among others. A reduction of citrate carrier activity was found in diabetic, hypothyroid, starved rats, and in rats fed on a polyunsaturated fatty acid (PUFA)-enriched diet. Most of these studies were performed by analyzing the activities of enzymes involved in FA synthesis in the cytosol of hepatocytes, such as ATP-citrate lyase, acetyl-CoA carboxylase, and FA synthetase. Activity and expression of these enzymes are modulated by FA composition of the diet. Acetyl-CoA carboxylase has also a regulatory role in hepatic FA synthesis because it represents the target of specific modulators, such as the metabolic intermediate citrate. Changes observed in the expression of the lipogenic enzymes acetyl-CoA carboxylase and fatty acid synthase were associated with a decrease in the activity of citrate carrier (CIC). Also the impairment of citrate transport was dependent on modification of the phospholipid composition of the mitochondrial membrane. Both qualitative and quantitative composition of dietary fat, for example, a prevalence of poly unsaturated fatty acids (PUFAs) with respect to the saturated fats, reduces hepatic lipogenesis, thereby exerting a beneficial effect in the case of cardiovascular diseases. Moreover, the carbohydrate amount in the diet is another factor capable of modifying hepatic lipogenesis. Little is known about the nutritional and hormonal abnormalities mainly insulin and T3 in regulation of CIC transport activity in obese patients.
Diet, Obesity, Insulin, Citrate Carrier Protein, Thyroxine, Lipogenic Enzymes
[1]
Alessandra Ferramosca and Vincenzo Zara, (2014). Dietary Fat and Hepatic Lipogenesis: Mitochondrial Citrate Carrier as a Sensorof Metabolic Changes1 American Society for Nutrition. Adv. Nutr. 5: 217–225.
[2]
Aluvila, S., Sun J., Harrison, D. H., Walters, D. E., Kaplan, R. S. (2010). Inhibitors of the mitochondrial citrate transport protein: validation of the role of substrate binding residues and discovery of the first purely competitive inhibitor. Mol Pharmacol. 77(1): 26-34.
[3]
Andrew M. Schaefer, Mark Walker, Douglass M. Turnbull, and Robert W. Taylor(2013). Endocrine disorders in mitochondrial disease. Mol Cell Endocrinol. 379(1-2): 2–11.
[4]
Aypak C, Türedi O, Yüce A, Görpelioğlu S. (2015). Thyroid-stimulating hormone (TSH) level in nutritionally obese children and metabolic co-morbidity. J Pediatr Endocrinol Metab. 26(7-8): 703-8.
[5]
Balestri P., Grosso S. Endocrine disorders in two sisters affected by MELAS syndrome (2000). J. Child Neurol. 15: 755–58.
[6]
Berio A., Piazzi A. (2006). A case of Kearns–Sayre sindrome with autoimmune thyroiditis and complete atrio-ventricular block. Min. Cardioangiol. 54: 387–391.
[7]
Bhalla K, Hwang BJ, Dewi RE, Ou L, Twaddel W, Fang HB, Vafai SB, Vazquez F, Puigserver P, Boros L,Girnun GD.(2011) PGC1α promotes tumor growth by inducing gene expression programs supporting lipogenesis. Cancer Res. 71(21): 6888-98.
[8]
Cánovas A, Rincón G, Islas-Trejo A, Jimenez-Flores R, Laubscher A, Medrano JF.(2013). RNA sequencing to study gene expression and single nucleotide polymorphism variation associated with citrate content in cow milk. J Dairy Sci. 96(4): 2637-48.
[9]
Cappello AR, Guido C, Santoro A, Santoro M, Capobianco L, Montanaro D, Madeo M, Andò S, Dolce V, Aquila S.(2012). The mitochondrial citrate carrier (CIC) is present and regulates insulin secretion by human male gamete. Endocrinology. 153(4): 1743-54.
[10]
Catalina-Rodriguez O, Kolukula VK, Tomita Y, Preet A, Palmieri F, Wellstein A, Byers S, Giaccia AJ,Glasgow E, Albanese C, Avantaggiati ML. (2012). The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis. Oncotarget. 3(10): 1220-35.
[11]
Damiano F, Gnoni GV, Siculella L. (2012). Citrate carrier promoter is target of peroxisome proliferator-activated receptor alpha and gamma in hepatocytes and adipocytes. Int J Biochem Cell Biol. 44(4): 659-68.
[12]
Damiano F, Mercuri E, Stanca E, Gnoni GV, Siculella L.. (2011) Streptozotocin-induced diabetes affects in rat liver citrate carrier gene expression by transcriptional and posttranscriptional mechanisms. Int J Biochem Cell Biol. 43(11): 1621-9.
[13]
De Pergola G, Ciampolillo A, Paolotti S, Trerotoli P, Giorgino R.(2007). Free triiodothyronine and thyroid stimulating hormone are directly associated with waist circumference, independently of insulin resistance, metabolic parameters and blood pressure in overweight and obese women. Clin Endocrinol (Oxf). 67(2): 265-9.
[14]
Di Donato S. (2009). Multisystem manifestations of mitochondrial disorders. J Neurol. 256(5): 693-710.
[15]
Edvardson S, Porcelli V, Jalas C, Soiferman D, Kellner Y, Shaag A, Korman SH, Pierri CL, Scarcia P,Fraenkel ND, Segel R, Schechter A, Frumkin A, Pines O, Saada A, Palmieri L, Elpeleg O. (2013). Agenesis of corpus callosum and optic nerve hypoplasia due to mutations in SLC25A1 encoding the mitochondrial citrate transporter. J Med Genet. 50(4): 240-5.
[16]
Ekbom K. (1975). Hereditary ataxia, photomyoclonus, skeletal deformities and lipoma. Acta Neurol. Scand. 51: 393–404.
[17]
Elena V. Grigorenko, W. Curtis Small, Lars-Olof Persson and Paul A. Srere. (1990). Citrate synthase 1 interacts with the citrate transporter of yeast mitochondria. Journal of Molecular Recognition. 3 (5-6): 215–219. Doi:10.1002/jmr.300030508.
[18]
El-Hattab AW, Emrick LT, Hsu JW, Chanprasert S, Jahoor F, Scaglia F, Craigen WJ. (2014). Glucose metabolism derangements in adults with the MELAS m.3243A>G mutation. Mitochondrion. 18: 63-9.
[19]
Elisa Morales. (2012). Obesity generates metabolic alterations in the myocardium leading to changes in mitochondrial membrane permeability. Conference Paper. Conference: Biochimica et Biophysica Acta (BBA) - Bioenergetics, At Germany, Volume: 181.
[20]
Ferramosca A, Conte A, Damiano F, Siculella L, Zara V. (2014). Differential effects of high-carbohydrate and high-fat diets on hepatic lipogenesis in rats. Eur J Nutr. 53(4): 1103-14.
[21]
Ferramosca A, Zara V. (2014). Dietary fat and hepatic lipogenesis: mitochondrial citrate carrier as a sensor of metabolic changes. Adv Nutr. 5(3): 217-25.
[22]
Ferramosca, A and Zara, V. (2014). Dietary fat and hepatic lipogenesis: mitochondrial citrate carrier as a sensor of metabolic changes. Adv Nutr. 5(3): 217-25.
[23]
Flores-Morales, A.; Gullberg, H.; Fernandez, L.; Ståhlberg, N.; Lee, N. H.; Vennström, B.;Norstedt, G. (2002). Patterns of liver gene expression governed by TRbeta. Mol. Endocrinol. 16, 1257-1260.
[24]
Friedman J. R., Webster B. M., Mastronarde D. N., Verhey K. J., Voeltz G. K. (2010). ER sliding dynamics and ER-mitochondrial contacts occur on acetylated microtubules. J Cell Biol. 190: 363–75.
[25]
Gabriele V. Gnoni1 , Paola Priore1 , Math J. H. Geelen2 and Luisa Siculella1(2009) Critical Review The Mitochondrial Citrate Carrier: Metabolic Role and Regulation of its Activity and Expression. IUBMB Life, 61(10): 987–994.
[26]
Giudetti A. M., Leo M., Siculella L, Gnoni G. V. (2006). Hypothyroidism down-regulates mitochondrial citrate carrier activity and expression in rat liver. Biochim Biophys Acta. 1761(4): 484-91.
[27]
Gnoni GV, Giudetti AM, Mercuri E, Damiano F, Stanca E, Priore P, Siculella L.(2010) Reduced activity and expression of mitochondrial citrate carrier in streptozotocin-induced diabetic rats. Endocrinology. 151(4): 1551-9.
[28]
Gnoni GV, Priore P, Geelen MJ, Siculella L. (2009). The mitochondrial citrate carrier: metabolic role and regulation of its activity and expression. IUBMB Life. 61(10): 987-94.
[29]
Goldmuntz, E., Wang, Z., Roe, B. A., Budarf, M. L. (1996). Cloning, genomic organization, and chromosomal localization of human citrate transport protein to the DiGeorge/velocardiofacial syndrome minimal critical region. Genomics 33: 271-276.
[30]
Iacobazzi, V., Lauria, G., Palmieri, F. (1997). Organization and sequence of the human gene for the mitochondrial citrate transport protein. DNA Seq. 7: 127-139.
[31]
Infantino, V.; Iacobazzi, V.; De Santis, F.; Mastrapasqua, M.; Palmieri, F. (2007). Transcription of the mitochondrial citrate carrier gene: Role of SREBP-1, upregulation by insulin and downregulation by PUFA. Biochem. Biophys. Res. Commun. 356, 249-254.
[32]
Iwasaki N, Babazono T, Tsuchiya K, Tomonaga O, Suzuki A, Togashi M, Ujihara N, Sakka Y, Yokokawa H, Ogata M,Nihei H, Iwamoto Y. (2001). Prevalence of A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA(Leu(UUR)) gene in Japanese patients with diabetes mellitus and end stage renal disease. J Hum Genet. 46(6): 330-4.
[33]
Jensen, M. V., Joseph, J. W., Ilkayeva, O., Burgess, S., Lu, D., Ronnebaum, S. M., Odegaard, M., Becker, T. C., Sherry, A. D., and Newgard, C. B. (2006). Compensatory responses to pyruvate carboxylase suppression in islet beta-cells. Preservation of glucose-stimulated insulin secretion. J. Biol. Chem. 281: 22342–51.
[34]
Kaplan, R. S., Mayor, J. A., Wood, D. O. (1993). The mitochondrial tricarboxylate transport protein: cDNA cloning, primary structure, and comparison with other mitochondrial transport proteins. J. Biol. Chem. 268: 13682-13690.
[35]
Kaplan, R. S.; Mayor, J. A.; Blackwell, R.; Maughon, R. H.; Wilson, G. L. (1991). The effect of insulin supplementation on diabetes-induced alterations in the extractable levels of functional mitochondrial anion transport proteins. Arch. Biochem Biophys. 287: 305-11.
[36]
Kaplan, R. S.; Oliveira, D. L.; Wilson, G. L. (1990). Streptozotocin-induced alterations in the levels of functional mitochondrial anion transport proteins. Arch. Biochem. Biophys. 280: 1811-1891.
[37]
Kolukula VK, Sahu G, Wellstein A, Rodriguez OC, Preet A, Iacobazzi V, D'Orazi G, Albanese C, Palmieri F,Avantaggiati ML. (2014). SLC25A1, or CIC, is a novel transcriptional target of mutant p53 and a negative tumor prognostic marker. Oncotarget. 5(5): 1212-25.
[38]
Kommareddy S, Lee SY, Braverman LE, Pearce EN. (2015). Thyroid function and metabolic syndrome: A cross-sectional study in obese and overweight patients. Endocr Pract. 21(11): 1204-10. doi: 10.4158/EP15739.
[39]
Kumar HK, Yadav RK, Prajapati J, Reddy CV, Raghunath M, Modi KD. (2009). Association between thyroid hormones, insulin resistance, and metabolic syndrome. Saudi Med J. 30(7): 907-11.
[40]
Kvetny J, Wilms L, Pedersen PL, Larsen J. (2010). Subclinical hypothyroidism affects mitochondrial function. Horm Metab Res. 42(5): 324-7.
[41]
Lau K. K., Yang S. P., Haddad M. N., Butani L., Makker S. P. (2007). Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes syndrome with hypothyroidism and focal segmental glomerulosclerosis in a paediatric patient. Int. J. Urol. Nephrol. 39: 941–946.
[42]
Lavieu G, Orci L, Shi L, Geiling M, Ravazzola M, Wieland F, Cosson P, Rothman J. E (2010). Induction of cortical endoplasmic reticulum by dimerization of a coatomer-binding peptide anchored to endoplasmic reticulum membranes. Proc Natl Acad Sci 107: 6876–81.
[43]
Lindinger PW, Christe M, Eberle AN, Kern B, Peterli R, Peters T, Jayawardene KJ, Fearnley IM, Walker JE. (2015). Important mitochondrial proteins in human omental adipose tissue show reduced expression in obesity. Data Brief. 23; 4: 40-3.
[44]
Lindroos B., Suuronen R., Miettinen S. (2011). The potential of adipose stem cells in regenerative medicine. Stem Cell Rev. 7: 269–291
[45]
Luna-Vazquez F, Cruz-Lumbreras R, Rodríguez-Castelán J, Cervantes-Rodríguez M, Rodríguez-Antolín J, Arroyo-Helguera O, Castelán F, Martínez-Gómez M, Cuevas E. (2014). Association between the serum concentration of triiodothyronine with components of metabolic syndrome, cardiovascular risk, and diet in euthyroid post-menopausal women without and with metabolic syndrome. Springerplus. 3: 266.
[46]
McFarland R., Taylor R. W., Turnbull D. M. (2010). A neurological perspective on mitochondrial disease. Lancet Neurol. 9: 829–840.
[47]
Mokuno T, Uchimura K, Hayashi R, Hayakawa N, Makino M, Nagata M, Kakizawa H, Sawai Y, Kotake M, Oda N, Nakai A, Nagasaka A, Itoh M.(1999). Glucose transporter 2 concentrations in hyper- and hypothyroid rat livers. J Endocrinol. 160(2): 285-9.
[48]
Morciano, P., Carrisi, C., Capobianco, L., Mannini, L., Burgio, G., Cestra, G., De Benedetto, G. E., Corona, D. F. V., Musio, A., Cenci, G. (2009). A conserved role for the mitochondrial citrate transporter Sea/SLC25A1 in the maintenance of chromosome integrity. Hum. Molec. Genet. 18: 4180-88.
[49]
Mynatt, R. L.; Park, E. A.; Thorngate, F. E.; Das, H. K.; Cook, G. A. (1994). Changes in carnitine palmitoyltransferase-I mRNA abundance produced by hyperthyroidism and hypothyroidism parallel changes in activity. Biochem. Biophys. Res. Commun. 201: 932-937.
[50]
Napoli E, Tassone F, Wong S, Angkustsiri K, Simon TJ, Song G, Giulivi C. (2015). Mitochondrial Citrate Transporter-Dependent Metabolic Signature in the 22q11.2 Deletion Syndrome. J Biol Chem. 290(38):23240-53. doi: 10.1074/jbc.M115.672360.
[51]
Nota B, Struys EA, Pop A, Jansen EE, Fernandez Ojeda MR, Kanhai WA, Kranendijk M, van Dooren SJ,Bevova MR, Sistermans EA, Nieuwint AW, Barth M, Ben-Omran T, Hoffmann GF, de Lonlay P, McDonald MT, Meberg A, Muntau AC, Nuoffer JM, Parini R, Read MH, Renneberg A, Santer R, Strahleck T, van Schaftingen E, van der Knaap MS, Jakobs C, Salomons GS.(2013). Deficiency in SLC25A1, encoding the mitochondrial citrate carrier, causes combined D-2- and L-2-hydroxyglutaric aciduria. Am J Hum Genet. 4; 92(4): 627-31.
[52]
Palmieri F. (2014). Mitochondrial transporters of the SLC25 family and associated diseases: a review. J Inherit Metab Dis. 37(4): 565-75.
[53]
Pitceathly R. D., Smith C., Fratter C., Alston C. L., He L. (2012). Craig K. Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics. Brain. 135: 3392–3403.
[54]
Ranieri M, Brajkovic S, Riboldi G, Ronchi D, Rizzo F, Bresolin N, Corti S, Comi GP. (2013). Mitochondrial fusion proteins and human diseases. Neurol Res Int. 2013: 293893.
[55]
Siculella L, Sabetta S, Giudetti AM, Gnoni GV. (2006). Hypothyroidism reduces tricarboxylate carrier activity and expression in rat liver mitochondria by reducing nuclear transcription rate and splicing efficiency J Biol Chem. 281(28): 19072-80.
[56]
Simon Edvardson, Vito Porcelli, Chaim Jalas, Devorah Soiferman, Yuval Kellner,Avraham Shaag, Stanley H Korman, Ciro Leonardo Pierri, Pasquale Scarcia,Nitay D Fraenkel, Reeval Segel, Abraham Schechter, Ayala Frumkin, Ophry Pines,Ann Saada, Luigi Palmieri, Orly Elpeleg. (2013). Agenesis of corpus callosum and optic nerve hypoplasia due to mutations in SLC25A1 encoding the mitochondrial citrate transporter. J Med Genet. 50: 240-245.
[57]
Stanhope KL (2015). Sugar consumption, metabolic disease and obesity: The state of the controversy. Crit Rev Clin Lab Sci. 17: 1-16.
[58]
Tarcin O, Abanonu GB, Yazici D, Tarcin O.(2012) Association of metabolic syndrome parameters with TT3 and FT3/FT4 ratio in obese Turkish population. Metab Syndr Relat Disord. 10(2): 137-42.
[59]
Topsakal S1, Yerlikaya E, Akin F, Kaptanoglu B, Erürker T.(2012). Relation with HOMA-IR and thyroid hormones in obese Turkish women with metabolic syndrome. Eat Weight Disord. 17(1): e57-61.
[60]
Uberbacher, E. C., Mural, R. J. (1991). Locating protein-coding regions in human DNA sequences by a multiple sensor-neural network approach. Proc. Nat. Acad. Sci. 88: 11261-11265.
[61]
Vid V. Flis and Günther Daum (2013). Lipid Transport between the Endoplasmic Reticulum and Mitochondria. Cold Spring Harb Perspect Biol. 5(6): a013235. Doi: 10.1101/cshperspect.a013235
[62]
Wilms L, Larsen J, Pedersen PL, Kvetny J.(2010). Evidence of mitochondrial dysfunction in obese adolescents. Acta Paediatr. 99(6): 906-11.
[63]
Zara V, Giudetti AM, Siculella L, Palmieri F, Gnoni GV. (2001). Covariance of tricarboxylate carrier activity and lipogenesis in liver of polyunsaturated fatty acid (n-6) fed rats. Eur J Biochem. 268(22): 5734-9.
[64]
Zorzano A, Claret M. (2015). Implications of mitochondrial dynamics on neurodegeneration and on hypothalamic dysfunction. Front Aging Neurosci. 7: 101.
