The metabolic adaptations to fasting in the liver are largely controlled by the nuclear hormone receptor peroxisome proliferator-activated receptor alpha (PPARα), where PPARα upregulates genes encoding the biochemical pathway for β-oxidation of fatty acids and ketogenesis. As part of an effort to identify and characterize nutritionally regulated genes that play physiological roles in the adaptation to fasting, we identified Major facilitator superfamily domain-containing protein 2a (Mfsd2a) as a fasting-induced gene regulated by both PPARα and glucagon signaling in the liver. MFSD2A is a cell-surface protein homologous to bacterial sodium-melibiose transporters. Hepatic expression and turnover of MFSD2A is acutely regulated by fasting/refeeding, but expression in the brain is constitutive. Relative to wildtype mice, gene-targeted Mfsd2a knockout mice are smaller, leaner, and have decreased serum, liver and brown adipose triglycerides. Mfsd2a knockout mice have normal liver lipid metabolism but increased whole body energy expenditure, likely due to increased β-oxidation in brown adipose tissue and significantly increased voluntary movement, but surprisingly exhibited a form of ataxia. Together, these results indicate that MFSD2A is a nutritionally regulated gene that plays myriad roles in body growth and development, motor function, and lipid metabolism. Moreover, these data suggest that the ligand(s) that are transported by MFSD2A play important roles in these physiological processes and await future identification.
References
[1]
Lazo M, Clark JM (2008) The epidemiology of nonalcoholic fatty liver disease: a global perspective. Semin Liver Dis 28: 339–350.
[2]
Flegal KM, Carroll MD, Ogden CL, Curtin LR (2010) Prevalence and trends in obesity among US adults, 1999–2008. JAMA 303: 235–241.
[3]
Yanovski SZ, Yanovski JA (2011) Obesity prevalence in the United States–up, down, or sideways? N Eng J Med 364: 987–989.
[4]
Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, et al. (2006) Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 113: 898–918.
[5]
Bonow RO, Eckel RH (2003) Diet, obesity, and cardiovascular risk. N Engl J Med 348: 2057–2058.
[6]
Hashimoto T, Fujita T, Usuda N, Cook W, Qi C, et al. (1999) Peroxisomal and mitochondrial fatty acid beta-oxidation in mice nullizygous for both peroxisome proliferator-activated receptor alpha and peroxisomal fatty acyl-CoA oxidase. Genotype correlation with fatty liver phenotype. J Biol Chem 274: 19228–19236.
Chakravarthy MV, Pan Z, Zhu Y, Tordjman K, Schneider JG, et al. (2005) “New” hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab 1: 309–322.
[9]
Rodriguez JC, Gil-Gomez G, Hegardt FG, Haro D (1994) Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids. J Biol Chem 269: 18767–18772.
[10]
Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, et al. (1999) Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest 103: 1489–1498.
[11]
Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84: 277–359.
[12]
Yen PM (2001) Physiological and molecular basis of thyroid hormone action. Physiol Rev 81: 1097–1142.
[13]
Nedergaard J, Bengtsson T, Cannon B (2011) New powers of brown fat: fighting the metabolic syndrome. Cell Metab 13: 238–240.
[14]
Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, et al. (2009) Functional brown adipose tissue in healthy adults. N Eng J Med 360: 1518–1525.
[15]
Kadereit B, Kumar P, Wang WJ, Miranda D, Snapp EL, et al. (2008) Evolutionarily conserved gene family important for fat storage. Proc Natl Acad Sci U S A 105: 94–99.
[16]
Reddy VS, Shlykov MA, Castillo R, Sun EI, Saier MH Jr (2012) The major facilitator superfamily (MFS) revisited. FEBS J 279: 2022–2035.
[17]
Angers M, Uldry M, Kong D, Gimble JM, Jetten AM (2008) Mfsd2a encodes a novel major facilitator superfamily domain-containing protein highly induced in brown adipose tissue during fasting and adaptive thermogenesis. Biochem J 416: 347–355.
[18]
Esnault C, Priet S, Ribet D, Vernochet C, Bruls T, et al. (2008) A placenta-specific receptor for the fusogenic, endogenous retrovirus-derived, human syncytin-2. Proc Natl Acad Sci U S A 105: 17532–17537.
[19]
Silver DL, Wang N, Tall AR (2000) Defective HDL particle uptake in ob/ob hepatocytes causes decreased recycling, degradation, and selective lipid uptake. J Clin Invest 105: 151–159.
[20]
Warming S, Costantino N, Court DL, Jenkins NA, Copeland NG (2005) Simple and highly efficient BAC recombineering using galK selection. Nucl Acids Res 33: e36-.
[21]
Gelling RW, Du XQ, Dichmann DS, Romer J, Huang H, et al. (2003) Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci U S A 100: 1438–1443.
[22]
Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, et al. (1995) Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol 15: 3012–3022.
[23]
McClive PJ, Sinclair AH (2001) Rapid DNA extraction and PCR-sexing of mouse embryos. Mol Reprod Dev 60: 225–226.
[24]
Johnston TP, Palmer WK (1993) Mechanism of poloxamer 407-induced hypertriglyceridemia in the rat. Biochem Pharmacol 46: 1037–1042.
[25]
Millar JS, Cromley DA, McCoy MG, Rader DJ, Billheimer JT (2005) Determining hepatic triglyceride production in mice: comparison of poloxamer 407 with Triton WR-1339. J Lipid Res 46: 2023–2028.
[26]
Gross DA, Snapp EL, Silver DL (2010) Structural insights into triglyceride storage mediated by fat storage-inducing transmembrane (FIT) protein 2. PLoS One 5: e10796.
[27]
Haemmerle G, Moustafa T, Woelkart G, Buttner S, Schmidt A, et al. (2011) ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-alpha and PGC-1. Nat Med 17: 1076–1085.
[28]
Blouet C, Schwartz GJ (2011) Nutrient-sensing hypothalamic TXNIP links nutrient excess to energy imbalance in mice. J Neurosci 31: 6019–6027.
[29]
Jaworski K, Ahmadian M, Duncan RE, Sarkadi-Nagy E, Varady KA, et al. (2009) AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency. Nat Med 15: 159–168.
[30]
Reiling JH, Clish CB, Carette JE, Varadarajan M, Brummelkamp TR, et al. (2011) A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter as a key mediator in the response to tunicamycin. Proc Natl Acad Sci U S A 108: 11756–11765.
[31]
Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, et al. (1998) Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 98: 2088–2093.
[32]
Ramnanan CJ, Edgerton DS, Kraft G, Cherrington AD (2011) Physiologic action of glucagon on liver glucose metabolism. Diabetes Obes Metab 13 Suppl 1: 118–125.
[33]
Vuguin PM, Charron MJ (2011) Novel insight into glucagon receptor action: lessons from knockout and transgenic mouse models. Diabetes Obes Metab 13 Suppl 1: 144–150.
[34]
Berglund ED, Lee-Young RS, Lustig DG, Lynes SE, Donahue EP, et al. (2009) Hepatic energy state is regulated by glucagon receptor signaling in mice. J Clin Invest 119: 2412–2422.
[35]
Longuet C, Sinclair EM, Maida A, Baggio LL, Maziarz M, et al. (2008) The glucagon receptor is required for the adaptive metabolic response to fasting. Cell Metab 8: 359–371.
[36]
Lin X, Yue P, Chen Z, Schonfeld G (2005) Hepatic triglyceride contents are genetically determined in mice: results of a strain survey. Am J Physiol 288: G1179–G1189.
[37]
Liang G, Yang J, Horton JD, Hammer RE, Goldstein JL, et al. (2002) Diminished Hepatic Response to Fasting/Refeeding and Liver X Receptor Agonists in Mice with Selective Deficiency of Sterol Regulatory Element-binding Protein-1c. J Biol Chem 277: 9520–9528.
[38]
Newberry EP, Xie Y, Kennedy S, Han X, Buhman KK, et al. (2003) Decreased Hepatic Triglyceride Accumulation and Altered Fatty Acid Uptake in Mice with Deletion of the Liver Fatty Acid-binding Protein Gene. J Biol Chem 278: 51664–51672.
[39]
Hughes ME, Hong HK, Chong JL, Indacochea AA, Lee SS, et al. (2012) Brain-specific rescue of clock reveals system-driven transcriptional rhythms in peripheral tissue. PLoS Genet 8: e1002835.
[40]
Rothwell NJ, Stock MJ (1979) A role for brown adipose tissue in diet-induced thermogenesis. Nature 281: 31–35.
[41]
Kozak LP (2010) Brown fat and the myth of diet-induced thermogenesis. Cell Metab 11: 263–267.
[42]
Fromme T, Klingenspor M (2011) Uncoupling protein 1 expression and high-fat diets. Am J Physiol Regul Integr Comp Physiol 300: R1–8.
[43]
Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, et al. (2011) Brown adipose tissue activity controls triglyceride clearance. Nat Med 17: 200–205.
[44]
Lopez M, Varela L, Vazquez MJ, Rodriguez-Cuenca S, Gonzalez CR, et al. (2010) Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 16: 1001–1008.
[45]
Chao PT, Yang L, Aja S, Moran TH, Bi S (2011) Knockdown of NPY expression in the dorsomedial hypothalamus promotes development of brown adipocytes and prevents diet-induced obesity. Cell Metab 13: 573–583.
[46]
Bamshad M, Song CK, Bartness TJ (1999) CNS origins of the sympathetic nervous system outflow to brown adipose tissue. Am J Physiol 276: R1569–R1578.
[47]
Nakamura K, Morrison SF (2011) Central efferent pathways for cold-defensive and febrile shivering. J Physiol 589: 3641–3658.
[48]
Carter RJ, Lione LA, Humby T, Mangiarini L, Mahal A, et al. (1999) Characterization of progressive motor deficits in mice transgenic for the human Huntington's disease mutation. J Neurosci 19: 3248–3257.
[49]
Lalonde R, Strazielle C (2011) Brain regions and genes affecting limb-clasping responses. Brain Res Rev 67: 252–259.
[50]
Lalonde R, Filali M, Bensoula AN, Lestienne F (1996) Sensorimotor learning in three cerebellar mutant mice. Neurobiol Learn Mem 65: 113–120.
[51]
Dupressoir A, Vernochet C, Bawa O, Harper F, Pierron G, et al. (2009) Syncytin-A knockout mice demonstrate the critical role in placentation of a fusogenic, endogenous retrovirus-derived, envelope gene. Proc Natl Acad Sci U S A 106: 12127–12132.
[52]
Dupressoir A, Vernochet C, Harper F, Guegan J, Dessen P, et al. (2011) A pair of co-opted retroviral envelope syncytin genes is required for formation of the two-layered murine placental syncytiotrophoblast. Proc Natl Acad Sci U S A 108: E1164–1173.
