Lipodystrophies—Disorders of the Fatty Tissue
Abstract
:1. Congenital Generalized Lipodystrophy
2. Genes in CGL
3. Partial Congenital Lipodystrophy
4. Genes in FPLD
5. Rare Diseases with Familial Partial Lipodystrophy
6. Acquired Generalized Lipodystrophy
7. Acquired Partial Lipodystrophy
8. Therapeutic Approaches for Lipodystrophy
9. Use of Animal Models to Determine Molecular Mechanisms in Lipodystrophy
10. Perspectives
Author Contributions
Funding
Conflicts of Interest
References
- Garg, A. Acquired and inherited lipodystrophies. N. Engl. J. Med. 2004, 350, 1220–1234. [Google Scholar] [CrossRef] [PubMed]
- Brown, R.J.; Araujo-Vilar, D.; Cheung, P.T.; Dunger, D.; Garg, A.; Jack, M.; Mungai, L.; Oral, E.A.; Patni, N.; Rother, K.I.; et al. The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline. J. Clin. Endocrinol. Metab. 2016, 101, 4500–4511. [Google Scholar] [CrossRef] [PubMed]
- Karadağ, A.S.; You, Y.; Danarti, R.; Al-Khuzaei, S.; Chen, W. Acanthosis nigricans and the metabolic syndrome. Clin. Dermatol. 2018, 36, 48–53. [Google Scholar] [CrossRef]
- Hayashi, Y.K.; Matsuda, C.; Ogawa, M.; Goto, K.; Tominaga, K.; Mitsuhashi, S.; Park, Y.E.; Nonaka, I.; Hino-Fukuyo, N.; Haginoya, K.; et al. Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy. J. Clin. Investig. 2009, 119, 2623–2633. [Google Scholar] [CrossRef] [PubMed]
- Agarwal, A.K.; Arioglu, E.; De Almeida, S.; Akkoc, N.; Taylor, S.I.; Bowcock, A.M.; Barnes, R.I.; Garg, A. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat. Genet. 2002, 31, 21–23. [Google Scholar] [CrossRef] [PubMed]
- Magré, J.; Delépine, M.; Khallouf, E.; Gedde-Dahl, T., Jr.; Van Maldergem, L.; Sobel, E.; Papp, J.; Meier, M.; Mégarbané, A.; Bachy, A.; et al. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat. Genet. 2001, 28, 365–370. [Google Scholar] [CrossRef]
- Kim, C.A.; Delépine, M.; Boutet, E.; El Mourabit, H.; Le Lay, S.; Meier, M.; Nemani, M.; Bridel, E.; Leite, C.C.; Bertola, D.R.; et al. Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J. Clin. Endocrinol. Metab. 2008, 93, 1129–1134. [Google Scholar] [CrossRef] [Green Version]
- Payne, F.; Lim, K.; Girousse, A.; Brown, R.J.; Kory, N.; Robbins, A.; Xue, Y.; Sleigh, A.; Cochran, E.; Adams, C.; et al. Mutations disrupting the Kennedy phosphatidylcholine pathway in humans with congenital lipodystrophy and fatty liver disease. Proc. Natl. Acad. Sci. USA 2014, 111, 8901–8906. [Google Scholar] [CrossRef] [Green Version]
- Chen, W.; Chang, B.; Saha, P.; Hartig, S.M.; Li, L.; Reddy, V.T.; Yang, Y.; Yechoor, V.; Mancini, M.A.; Chan, L. Berardinelli-Seip congenital lipodystrophy 2/seipin is a cell-autonomous regulator of lipolysis essential for adipocyte differentiation. Mol. Cell Biol. 2012, 32, 1099–1111. [Google Scholar] [CrossRef] [Green Version]
- Rajab, A.; Straub, V.; McCann, L.J.; Seelow, D.; Varon, R.; Barresi, R.; Schulze, A.; Lucke, B.; Lützkendorf, S.; Karbasiyan, M.; et al. Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4) due to PTRF-CAVIN mutations. PLoS Genet. 2010, 6, e1000874. [Google Scholar] [CrossRef] [Green Version]
- Knebel, B.; Kotzka, J.; Lehr, S.; Hartwig, S.; Avci, H.; Jacob, S.; Nitzgen, U.; Schiller, M.; März, W.; Hoffmann, M.M.; et al. A mutation in the c-fos gene associated with congenital generalized lipodystrophy. Orphanet J. Rare Dis. 2013, 8, 119. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Herbst, K.L.; Tannock, L.R.; Deeb, S.S.; Purnell, J.Q.; Brunzell, J.D.; Chait, A. Kobberling type of familial partial lipodystrophy: An underrecognized syndrome. Diabetes Care 2003, 26, 1819–1824. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cao, H.; Hegele, R.A. Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum. Mol. Genet. 2000, 9, 109–112. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shackleton, S.; Lloyd, D.J.; Jackson, S.N.; Evans, R.; Niermeijer, M.F.; Singh, B.M.; Schmidt, H.; Brabant, G.; Kumar, S.; Durrington, P.N.; et al. LMNA, encoding lamin A/C.; is mutated in partial lipodystrophy. Nat. Genet. 2000, 24, 153–156. [Google Scholar] [CrossRef]
- Dyment, D.A.; Gibson, W.T.; Huang, L.; Bassyouni, H.; Hegele, R.A.; Innes, A.M. Biallelic mutations at PPARgamma cause a congenital.; generalized lipodystrophy similar to the Berardinelli-Seip syndrome. Eur. J. Med. Genet. 2014, 57, 524–526. [Google Scholar] [CrossRef]
- Semple, R.K.; Chatterjee, V.K.; O’Rahilly, S. PPAR gamma and human metabolic disease. J. Clin. Investig. 2006, 116, 581–589. [Google Scholar] [CrossRef] [Green Version]
- Rubio-Cabezas, O.; Puri, V.; Murano, I.; Saudek, V.; Semple, R.K.; Dash, S.; Hyden, C.S.; Bottomley, W.; Vigouroux, C.; Magré, J.; et al. Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Mol. Med. 2009, 1, 280–287. [Google Scholar] [CrossRef]
- Albert, J.S.; Yerges-Armstrong, L.M.; Horenstein, R.B.; Pollin, T.I.; Sreenivasan, U.T.; Chai, S.; Blaner, W.S.; Snitker, S.; O’Connell, J.R.; Gong, D.W.; et al. Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes. N. Engl. J. Med. 2014, 370, 2307–2315. [Google Scholar] [CrossRef] [Green Version]
- Gandotra, S.; Le Dour, C.; Bottomley, W.; Cervera, P.; Giral, P.; Reznik, Y.; Charpentier, G.; Auclair, M.; Delépine, M.; Barroso, I.; et al. Perilipin deficiency and autosomal dominant partial lipodystrophy. N. Engl. J. Med. 2011, 364, 740–748. [Google Scholar] [CrossRef] [Green Version]
- Garg, A.; Kircher, M.; Del Campo, M.; Amato, R.S.; Agarwal, A.K. Whole exome sequencing identifies de novo heterozygous CAV1 mutations associated with a novel neonatal onset lipodystrophy syndrome. Am. J. Med. Genet. 2015, 167, 1796–1806. [Google Scholar] [CrossRef] [Green Version]
- Farhan, S.M.; Robinson, J.F.; McIntyre, A.D.; Marrosu, M.G.; Ticca, A.F.; Loddo, S.; Carboni, N.; Brancati, F.; Hegele, R.A. A novel LIPE nonsense mutation found using exome sequencing in siblings with lateonset familial partial lipodystrophy. Can. J. Cardiol. 2014, 30, 1649–1654. [Google Scholar] [CrossRef] [PubMed]
- George, S.; Rochford, J.J.; Wolfrum, C.; Gray, S.L.; Schinner, S.; Wilson, J.C.; Soos, M.A.; Murgatroyd, P.R.; Williams, R.M.; Acerini, C.L.; et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 2004, 304, 1325–1328. [Google Scholar] [CrossRef] [Green Version]
- Granneman, J.G.; Moore, H.P.; Krishnamoorthy, R.; Rathod, M. Perilipin controls lipolysis by regulating the interactions of AB-hydrolase containing 5 (Abhd5) and adipose triglyceride lipase (Atgl). J. Biol. Chem. 2009, 284, 34538–34544. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shen, W.J.; Patel, S.; Miyoshi, H.; Greenberg, A.S.; Kraemer, F.B. Functional interaction of hormone-sensitive lipase and perilipin in lipolysis. J. Lipid Res. 2009, 50, 2306–2313. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tansey, J.T.; Sztalryd, C.; Hlavin, E.M.; Kimmel, A.R.; Londos, C. The central role of perilipin a in lipid metabolism and adipocyte lipolysis. IUBMB Life 2004, 56, 379–385. [Google Scholar] [CrossRef] [PubMed]
- Walther, T.C.; Chung, J.; Farese, R.V. Lipid droplet biogenesis. Annu. Rev. Cell Dev. Biol. 2017, 33, 491–510. [Google Scholar] [CrossRef] [Green Version]
- Novelli, G.; Muchir, A.; Sangiuolo, F.; Helbling-Leclerc, A.; D’Apice, M.R.; Massart, C.; Capon, F.; Sbraccia, P.; Federici, M.; Lauro, R.; et al. Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am. J. Hum. Genet. 2002, 71, 426–431. [Google Scholar] [CrossRef] [Green Version]
- Agarwal, A.K.; Fryns, J.P.; Auchus, R.J.; Garg, A. Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum. Mol Genet. 2003, 12, 1995–2001. [Google Scholar] [CrossRef]
- Thauvin-Robinet, C.; Auclair, M.; Duplomb, L.; Caron-Debarle, M.; Avila, M.; St-Onge, J.; Le Merrer, M.; Le Luyer, B.; Héron, D.; Mathieu-Dramard, M.; et al. PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy. Am. J. Hum. Genet. 2013, 93, 141–149. [Google Scholar] [CrossRef] [Green Version]
- Lessel, D.; Ozel, A.B.; Campbell, S.E.; Saadi, A.; Arlt, M.F.; McSweeney, K.M.; Plaiasu, V.; Szakszon, K.; Szollos, A.; Rusu, C.; et al. Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations. Hum. Genet. 2018, 137, 921–939. [Google Scholar] [CrossRef]
- Eriksson, M.; Brown, W.T.; Gordon, L.B.; Glynn, M.W.; Singer, J.; Scott, L.; Erdos, M.R.; Robbins, C.M.; Moses, T.Y.; Berglund, P.; et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 2003, 423, 293–298. [Google Scholar] [CrossRef] [Green Version]
- Misra, A.; Peethambaram, A.; Garg, A. Clinical features and metabolic and autoimmune derangements in acquired partial lipodystrophy: Report of 35 cases and review of the literature. Medicine 2004, 83, 18–34. [Google Scholar] [CrossRef]
- Misra, A.; Garg, A. Clinical features and metabolic derangements in acquired generalized lipodystrophy: Case reports and review of the literature. Medicine 2003, 82, 129–146. [Google Scholar] [CrossRef] [PubMed]
- Chen, D.; Misra, A.; Garg, A. Clinical review 153: Lipodystrophy in human immunodeficiency virus-infected patients. J. Clin. Endocrinol. Metab. 2002, 87, 4845–4856. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Grinspoon, S.; Carr, A. Cardiovascular risk and body-fat abnormalities in HIV infected adults. N. Engl. J. Med. 2005, 352, 48–62. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Savage, D.B.; Semple, R.K.; Clatworthy, M.R.; Lyons, P.A.; Morgan, B.P.; Cochran, E.K.; Gorden, P.; Raymond-Barker, P.; Murgatroyd, P.R.; Adams, C.; et al. Complement abnormalities in acquired lipodystrophy revisited. J. Clin. Endocrinol. Metab. 2009, 94, 10–16. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hudon, S.E.; Coffinier, C.; Michaelis, S.; Fong, L.G.; Young, S.G.; Hrycyna, C.A. HIV-protease inhibitors block the enzymatic activity of purified Ste24p. Biochem. Biophys. Res. Commun. 2008, 374, 365–368. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, H.; Hanes, J.; Johnson, K.A. Toxicity of nucleoside analogues used to treat AIDS and the selectivity of the mitochondrial DNA polymerase. Biochemistry 2003, 42, 14711–14719. [Google Scholar] [CrossRef] [PubMed]
- Andersen, O. A characterisation of low-grade inflammation and metabolic complications in HIV-infected patients. Review Dan. Med. J. 2016, 63, B5291. [Google Scholar]
- Tsoukas, M.A.; Farr, O.M.; Mantzoros, C.S. Leptin in congenital and HIV-associated lipodystrophy. Metabolism 2015, 64, 47–59. [Google Scholar] [CrossRef] [PubMed]
- Brown, R.J.; Oral, E.A.; Cochran, E.; Araújo-Vilar, D.; Savage, D.B.; Long, A.; Fine, G.; Salinardi, T.; Gorden, P. Long-term effectiveness and safety of metreleptin in the treatment of patients with generalized lipodystrophy. Endocrine 2018, 60, 479–489. [Google Scholar] [CrossRef] [PubMed]
- Akinci, B.; Meral, R.; Oral, E.A. Update on therapeutic options in lipodystrophy. Curr. Diab. Rep. 2018, 18, 139. [Google Scholar] [CrossRef]
- Friedman, J.M.; Mantzoros, C.S. 20 years of leptin: From the discovery of the leptin gene to leptin in our therapeutic armamentarium. Metabolism 2015, 64, 1–4. [Google Scholar] [CrossRef] [PubMed]
- Bagias, C.; Xiarchou, A.; Bargiota, A.; Tigas, S. Familial Partial Lipodystrophy (FPLD): Recent Insights. Diabetes Metab. Syndr. Obes. 2020, 13, 1531–1544. [Google Scholar] [CrossRef] [PubMed]
- Simpson, F.; Whitehead, J.P. Adiponectin-it’s all about the modifications. Int. J. Biochem. Cell Biol. 2010, 42, 785–788. [Google Scholar] [CrossRef] [PubMed]
- Shea, J.; Terry, C.; Edwards, K.; Agarwal, J. Glitazone loaded fat enhances adiponectin production and inhibits breast cancer cell proliferation. Mol. Biol. Rep. 2019, 46, 6485–6494. [Google Scholar] [CrossRef]
- Paruthi, J.; Gill, N.; Mantzoros, C.S. Adipokines in the HIV/HAART-associated lipodystrophy syndrome. Metabolism 2013, 62, 1199–1205. [Google Scholar] [CrossRef]
- Blümer, R.M.; van der Valk, M.; Ackermans, M.; Endert, E.; Serlie, M.J.; Reiss, P.; Sauerwein, H.P. A rosiglitazone-induced increase in adiponectin does not improve glucose metabolism in HIV-infected patients with overt lipoatrophy. Am. J. Physiol. Endocrinol. Metab. 2009, 297, E1097–E1104. [Google Scholar] [CrossRef]
- Banning, F.; Rottenkolber, M.; Freibothe, I.; Seissler, J.; Lechner, A. Insulin secretory defect in familial partial lipodystrophy type 2 and successful long-term treatment with a glucagon-like peptide 1 receptor agonist. Diabet. Med. 2017, 34, 1792–1794. [Google Scholar] [CrossRef]
- Valerio, C.M.; de Almeida, J.S.; Moreira, R.O.; Aguiar, L.B.S.; Siciliano, P.O.; Carvalho, D.P.; Godoy-Matos, A.F. Dipeptidyl peptidase-4 levels are increased and partially related to body fat distribution in patients with familial partial lipodystrophy type 2. Diabetol. Metab. Syndr. 2017, 9, 26. [Google Scholar] [CrossRef] [Green Version]
- Oliveira, J.; Lau, E.; Carvalho, D.; Freitas, P. Glucagon-like peptide-1 analogues-an efficient therapeutic option for the severe insulin resistance of lipodystrophic syndromes: Two case reports. J. Med. Case Rep. 2017, 11, 12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hamaguchi, T.; Hirota, Y.; Takeuchi, T.; Nakagawa, Y.; Matsuoka, A.; Matsumoto, M.; Awano, H.; Iijima, K.; Cha, P.C.; Satake, W.; et al. Treatment of a case of severe insulin resistance as a result of a PIK 3R1 mutation with a sodium–glucose cotransporter 2 inhibitor. J. Diabetes Investig. 2018, 9, 1224–1227. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Polyzos, S.A.; Mantzoros, C.S. Lipodystrophy: Time for a global registry and randomized clinical trials to assess efficacy, safety and cost-effectiveness of established and novel medications. Metabolism 2017, 72, A4–A10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, L.; Jiang, Q.; Wang, X.; Zhang, Y.; Lin, R.C.; Lam, S.M.; Shui, G.; Zhou, L.; Li, P.; Wang, Y.; et al. Adipose-specific knockout of SEIPIN/BSCL2 results in progressive lipodystrophy. Diabetes 2014, 63, 2320–2331. [Google Scholar] [CrossRef] [Green Version]
- Zhuang, H.; Zhang, X.; Zhu, C.; Tang, X.; Yu, F.; Shang, G.W.; Cai, X. Molecular mechanisms of PPAR-gamma governing MSC osteogenic and adipogenic differentiation. Curr. Stem Cell Res. Ther. 2016, 11, 255–264. [Google Scholar] [CrossRef]
- Barak, Y.; Nelson, M.C.; ong, E.S.; Jones, Y.Z.; Ruiz-Lozano, P.; Chien, K.R.; Evans, R.M. PPARγ is required for placental, cardiac, and adipose tissue development. Mol. Cell 1999, 4, 585–595. [Google Scholar] [CrossRef]
- Duan, S.Z.; Ivashchenko, C.Y.; Whitesall, S.E.; D’Alecy, L.G.; Duquaine, D.C.; Brosius, F.C., III; Gonzales, F.J.; Vinson, C.; Pierre, M.A.; Milstone, D.S.; et al. Hypotension, lipodystrophy, and insulin resistance in generalized PPARγ-deficient mice rescued from embryonic lethality. J. Clin. Investig. 2007, 117, 812–822. [Google Scholar] [CrossRef] [Green Version]
- Koutnikova, H.; Cock, T.-A.; Watanabe, M.; Houten, S.M.; Champy, M.-F.; Dierich, A.; Auwerx, J. Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPAR gamma hypomorphic mice. Proc. Natl. Acad. Sci. USA 2003, 100, 14457–14462. [Google Scholar] [CrossRef] [Green Version]
- He, W.; Barak, Y.; Hevener, A.; Olson, P.; Liao, D.; Le, J.; Nelson, M.; Ong, E.; Olefsky, J.M.; Evans, R.M. Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proc. Natl. Acad. Sci. USA 2003, 100, 15712–15717. [Google Scholar] [CrossRef] [Green Version]
- Savage, D.B.; Murgatroyd, P.R.; Chatterjee, V.K.; O’Rahilly, S. Energy expenditure and adaptive responses to an acute hypercaloric fat load in humans with lipodystrophy. J. Clin. Endocrinol. Metab. 2005, 90, 1446–1452. [Google Scholar] [CrossRef] [Green Version]
- Vogel, P.; Read, R.; Hansen, G.; Wingert, J.; Dacosta, C.M.; Buhring, L.M.; Shadoan, M. Pathology of congenital generalized lipodystrophy in Agpat2−/− mice. Vet. Pathol. 2011, 48, 642–654. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tapia, P.J.; Figueroa, A.M.; Eisner, V.; González-Hódar, L.; Robledo, F.; Agarwal, A.K.; Garg, A.; Cortés, V. Absence of AGPAT2 impairs brown adipogenesis, increases IFN stimulated gene expression and alters mitochondrial morphology. Metabolism 2020, 111, 154341. [Google Scholar] [CrossRef] [PubMed]
- Cortés, V.A.; Curtis, D.E.; Sukumaran, S.; Shao, X.; Parameswara, V.; Rashid, S.; Smith, A.R.; Ren, J.; Esser, V.; Hammer, R.E.; et al. Molecular mechanisms of hepatic steatosis and insulin resistance in the AGPAT2-deficient mouse model of congenital generalized lipodystrophy. Cell Metab. 2009, 9, 165–176. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Subauste, A.R.; Das, A.K.; Li, X.; Elliott, B.G.; Evans, C.; Azzouny, M.E.; Treutelaar, M.; Oral, E.; Leff, T.; Burant, C.F. Alterations in lipid signaling underlie lipodystrophy secondary to AGPAT2 mutations. Diabetes 2012, 61, 2922–2931. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Moitra, J.; Mason, M.M.; Olive, M.; Krylov, D.; Gavrilova, O.; Marcus-Samuels, B.; Feigenbaum, L.; Lee, E.; Aoyama, T.; Eckhaus, M.; et al. Life without white fat: A transgenic mouse. Genes Dev. 1998, 12, 3168–3181. [Google Scholar] [CrossRef] [Green Version]
- Shimomura, I.; Bashmakov, Y.; Horton, J.D. Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus. J. Biol. Chem. 1999, 274, 30028–30032. [Google Scholar] [CrossRef] [Green Version]
- Mounkes, L.C.; Kozlov, S.; Hernandez, L.; Sullivan, T.; Stewart, C.L. A progeroid syndrome in mice is caused by defects in A-type lamins. Nature 2003, 423, 298–301. [Google Scholar] [CrossRef]
- Vadrot, N.; Duband-Goulet, I.; Cabet, E.; Attanda, W.; Barateau, A.; Vicart, P.; Gerbal, F.; Briand, N.; Vigouroux, C.; Oldenburg, A.R.; et al. The p.R482W substitution in A-type lamins deregulates SREBP-1 activity in Dunnigan-type familial partial lipodystrophy. Hum. Mol. Genet. 2015, 24, 2096–2109. [Google Scholar] [CrossRef] [Green Version]
- Lloyd, D.J.; Trembath, R.C.; Shackleton, S. A novel interaction between lamin A and SREBP1: Implications for partial lipodystrophy and other laminopathies. Hum. Mol. Genet. 2002, 11, 769–777. [Google Scholar] [CrossRef] [Green Version]
- Rochford, J.J. Mouse models of lipodystrophy and their significance in understanding fat regulation. Curr. Top. Dev. Biol. 2014, 109, 53–96. [Google Scholar]
- Bertrand, A.T.; Renou, L.; Papadopoulos, A.; Beuvin, M.; Lacène, E.; Massart, C.; Ottolenghi, C.; Decostre, V.; Maron, S.; Schlossarek, S.; et al. DelK32-lamin A/C has abnormal location and induces incomplete tissue maturation and severe metabolic defects leading to premature death. Hum. Mol. Genet. 2012, 21, 1037–1048. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jelenik, T.; Kaul, K.; Séquaris, G.; Flögel, U.; Phielix, E.; Kotzka, J.; Knebel, B.; Fahlbusch, P.; Hörbelt, T.; Lehr, S.; et al. Mechanisms of Insulin Resistance in Primary and Secondary Nonalcoholic Fatty Liver. Diabetes 2017, 66, 2241–2253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Knebel, B.; Haas, J.; Hartwig, S.; Jacob, S.; Köllmer, C.; Nitzgen, U.; Muller-Wieland, D.; Kotzka, J. Liver-specific expression of transcriptionally active SREBP-1c is associated with fatty liver and increased visceral fat mass. PLoS ONE 2012, 7, e31812. [Google Scholar] [CrossRef] [Green Version]
- Kotzka, J.; Knebel, B.; Haas, J.; Kremer, L.; Jacob, S.; Hartwig, S.; Nitzgen, U.; Muller-Wieland, D. Preventing phosphorylation of sterol regulatory element-binding protein 1a by MAP-kinases protects mice from fatty liver and visceral obesity. PLoS ONE 2012, 7, e32609. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, G.Y.; Sabatini, D.M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 2020, 21, 183–203. [Google Scholar] [CrossRef] [PubMed]
- Charar, C.; Gruenbaum, Y. Lamins and metabolism. Clin. Sci. 2017, 131, 105–111. [Google Scholar] [CrossRef] [PubMed]
- Ramos, F.J.; Chen, S.C.; Garelick, M.G.; Dai, D.-F.; Liao, C.-Y.; Schreiber, K.H.; MacKay, V.L.; An, E.H.; Strong, R.; Ladiges, W.C.; et al. Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function, and extends survival. Sci. Transl. Med. 2012, 4, 144ra103. [Google Scholar] [CrossRef] [Green Version]
- Martinez-Botas, J.; Anderson, J.B.; Tessier, D.; Lapillonne, A.; Chang, B.H.; Quast, M.J.; Gorenstein, D.; Chen, K.H.; Chan, L. Absence of perilipin results in leanness and reverses obesity in Lepr(db/db) mice. Nat. Genet. 2000, 26, 474–479. [Google Scholar] [CrossRef]
- Tansey, J.T.; Sztalryd, C.; Gruia-Gray, J.; Roush, D.L.; Zee, J.V.; Gavrilova, O.; Reitman, M.L.; Deng, C.X.; Li, C.; Kimmel, A.R.; et al. Perilipin ablation results in a lean mouse with aberrant adipocyte lipolysis, enhanced leptin production, and resistance to diet-induced obesity. Proc. Natl. Acad. Sci. USA 2001, 98, 6494–6499. [Google Scholar] [CrossRef] [Green Version]
- Saha, P.K.; Kojima, H.; Martinez-Botas, J.; Sunehag, A.L.; Chan, L. Metabolic adaptations in the absence of perilipin: Increased beta-oxidation and decreased hepatic glucose production associated with peripheral insulin resistance but normal glucose tolerance in perilipin-null mice. J. Biol. Chem. 2004, 279, 35150–35158. [Google Scholar] [CrossRef] [Green Version]
- Nishino, N.; Tamori, Y.; Tateya, S.; Kawaguchi, T.; Shibakusa, T.; Mizunoya, W.; Inoue, K.; Kitazawa, R.; Kitazawa, S.; Matsuki, Y.; et al. FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets. J. Clin. Investig. 2008, 118, 2808–2821. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hedbacker, K.; Lu, Y.-H.; Dallner, O.; Li, Z.; Fayzikhodjaeva, G.; Birsoy, K.; Han, C.; Yang, C.; Friedman, J.M. Limitation of adipose tissue by the number of embryonic progenitor cells. eLife 2020, 9, e53074. [Google Scholar] [CrossRef] [PubMed]
- Dean, J.M.; He, A.; Tan, M.; Wang, J.; Lu, D.; Razani, B.; Lodhi, I.J. MED19 Regulates Adipogenesis and Maintenance of White Adipose Tissue Mass by Mediating PPARγ-Dependent Gene Expression. Cell Rep. 2020, 33, 108228. [Google Scholar] [CrossRef] [PubMed]
- Shimano, H.; Sato, R. SREBP-regulated lipid metabolism: Convergent physiology-divergent pathophysiology. Nat. Rev. Endocrinol. 2017, 13, 710–730. [Google Scholar] [CrossRef] [PubMed]
- Jones, S. An overview of the basic helix-loop-helix proteins. Genome Biol. 2004, 5, 226. [Google Scholar] [CrossRef] [Green Version]
- Engelking, L.J.; Cantoria, M.J.; Xu, Y.; Liang, G. Developmental and extrahepatic physiological functions of SREBP pathway genes in mice. Semin. Cell Dev. Biol. 2018, 81, 98–109. [Google Scholar] [CrossRef] [PubMed]
- Shimano, H.; Horton, J.D.; Hammer, R.E.; Shimomura, I.; Brown, M.S.; Goldstein, J.L. Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J. Clin. Investig. 1996, 98, 1575–1584. [Google Scholar] [CrossRef] [Green Version]
- Shimano, H.; Horton, J.D.; Shimomura, I.; Hammer, R.E.; Brown, M.S.; Goldstein, J.L. Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J. Clin. Investig. 1997, 99, 846–854. [Google Scholar] [CrossRef] [Green Version]
- Shimano, H.; Shimomura, I.; Hammer, R.E.; Herz, J.; Goldstein, J.L.; Brown, M.S.; Horton, J.D. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. J. Clin. Investig. 1997, 100, 2115–2124. [Google Scholar] [CrossRef] [Green Version]
- Shimomura, I.; Hammer, R.E.; Richardson, J.A.; Ikemoto, S.; Bashmakov, Y.; Goldstein, J.L.; Brown, M.S. Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: Model for congenital generalized lipodystrophy. Genes Dev. 1998, 12, 3182–3194. [Google Scholar] [CrossRef] [Green Version]
- Kim, J.B.; Spiegelman, B.M. ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev. 1996, 10, 1096–1107. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Type | Pathophysiology | Clinical Appearance | Phenotype (OMIM) | Gene (OMIM) |
---|---|---|---|---|
Congenital generalized lipodystrophy (CGL) | AGPAT is a key enzyme in triglyceride and phospholipid biosynthesis. | Lack of fatty tissue at birth. | CGL1 (#608594) | AGPAT2 (#603100) |
Seipin/BSCL2 plays a role in fat droplet formation. | Absence of fatty tissue at birth; cardiomyopathy. | CGL2 (#269700) | BSCL2 (#606158) | |
Caveolin is an integral part of the caveolae | Lack of fatty tissue at birth; dwarfism. | CGL3 (#612526) | CAV1 (#601047) | |
Cavin is involved in the biogenesis of the caveolae | Absence of fatty tissue at birth; cardiomyopathy. | CGL4 (#613327) | CAVIN1 (#603198) | |
Mandibuloacral dysplasia (MAD) | Lamin A and C are nuclear lamina proteins. | Absence of the subcutaneous fatty tissue of the extremities. | MADA (#248370) | LMNA (#150330) |
ZMPSTE24 processes pre-lamin A into lamin A. | Generalized loss of fat. | MADB (#608612) | ZMPSTE24 (#606480) | |
Familial partial lipodystrophy (FPL) | Cell Death-Inducing DFFA-like Effector C is a fat droplet associated protein that inhibits lipolysis. | Lack of fat in the lower extremities and metabolic disorders. | FPLD5 (#615238) | CIDEC (#612120) |
Hormone-sensitive lipase has a central role in the lipolysis of fat in adipocytes. | Lack of fat in the lower extremities and metabolic disorders. | FPLD6 (#615980) | LIPE (#151750) | |
Wiedemann-Rautenstrauch syndrome | RNA Polymerase III subunit C1 is the largest subunit of RNA Polymerase III | Characterized by short stature, generalized absence of fatty tissue and progeria. | WDRTS (#264090) | POLR3A (#614258) |
Néstor-Guillermo progeria syndrome | Barrier-to-autointegration factor 1 dislocates lamin A from the nuclear envelope. | Generalized lipodystrophy with disorders of bone metabolism. | NGPS (#614008) | BANF1 (#603811) |
Ruijs-Aalfs syndrome | SprT-like N-terminal domain protein is part of the DNA repair system. | Generalized lipodystrophy with hepatocellular carcinoma. | RJALS (#616200) | SPRTN (#616086) |
Cockayne syndrome | Excision Repair Cross-Complementing Group 8 is part of the DNA repair system. | Generalized lipodystrophy with neurodegenerative disorders. | CSA (#216400) | ERCC8 (#609412) |
Excision Repair Cross-Complementing Group 6 is part of the DNA repair system. | Generalized lipodystrophy with neurodegenerative disorders. | CSB (#133540) | ERCC6 (#609413) |
Type | Pathophysiology | Clinical Appearance | Phenotype (OMIM) | Gene (OMIM) |
---|---|---|---|---|
Familial partial lipodystrophy (FPL) | Lack of fat on the lower and upper extremities, buttocks and abdomen and metabolic disorders. | FPLD1, Kobberling (#608600) | Unknown | |
Lamin A and C are nuclear lamina proteins. | Lack of fat on the lower and upper extremities, buttocks and abdomen and metabolic disorders. | FPLD2, Dunnigan (#151660) | LMNA (#150330) | |
Peroxisome proliferator-activated receptor gamma is a central transcription factor in adipocyte differentiation. | Lack of fat in the lower and upper extremities and metabolic disorders. | FPLD3 (#604367) | PPARγ (#601487) | |
Perilipin is a hormonally regulated phosphoprotein that is located at the fat droplets. | Lack of fat in the lower extremities and metabolic disorders. | FPLD4 (#613877) | PLIN1 (#170290) | |
Caveolin is an integral part of the caveolae. | Atypical partial lipodystrophy with cataract and spasms in lower extremities. | FPLD7 (#606721) | CAV1 (#601047) | |
Protein kinase B beta is a central signal protein downstream of the insulin receptor. | Lack of fat in the lower extremities and metabolic disorders. | ACT2-coupled lipodystrophy (# 240900) | ACT2 (#164731) | |
Hutchinson-Gilford progeria syndrome | Lamin A and C are nuclear lamina proteins. | Characterized by short stature, low body weight, generalized lack of fatty tissue and progeria. | HGPS (#176670) | LMNA (#150330) |
SHORT syndrome | Phosphatidylinositol 3-kinase, Regulatory Subunit 1 (p85) is part of phosphatidylinositol 3-kinase and is a key protein in the cellular signal extension of insulin. | Dwarfism with partial absence of fatty tissue. | SHORT (#269880) | PIK3R1 (#171833) |
Mandibular hypoplasia | Polymerase delta 1 encodes the catalytic subunit of DNA polymerase delta. | Absence of subcutaneous fatty tissue and metabolic abnormalities. | MDPL (#615381) | POLD1 (#174761) |
Keppen-Lubinsky syndrome | Phosphatidylinositol 3-kinase, Regulatory Subunit 1 (p85) is part of phosphatidylinositol 3-kinase and is a key protein in the cellular signal extension of insulin. | Generalized lipodystrophy with disorders in psychomotor development. | KPLBS (#614098) | KCNJ6 (#600877) |
Marfan Lipodystrophie syndrome | Fibrillin is a major component of the extracellular matrix. | Generalized lipodystrophy with growth abnormalities. | MFLS (#616914) | FBN1 (#134797) |
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Knebel, B.; Müller-Wieland, D.; Kotzka, J. Lipodystrophies—Disorders of the Fatty Tissue. Int. J. Mol. Sci. 2020, 21, 8778. https://doi.org/10.3390/ijms21228778
Knebel B, Müller-Wieland D, Kotzka J. Lipodystrophies—Disorders of the Fatty Tissue. International Journal of Molecular Sciences. 2020; 21(22):8778. https://doi.org/10.3390/ijms21228778
Chicago/Turabian StyleKnebel, Birgit, Dirk Müller-Wieland, and Jorg Kotzka. 2020. "Lipodystrophies—Disorders of the Fatty Tissue" International Journal of Molecular Sciences 21, no. 22: 8778. https://doi.org/10.3390/ijms21228778
APA StyleKnebel, B., Müller-Wieland, D., & Kotzka, J. (2020). Lipodystrophies—Disorders of the Fatty Tissue. International Journal of Molecular Sciences, 21(22), 8778. https://doi.org/10.3390/ijms21228778