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Congenital Generalized Lipodystrophy Lima JG, Dos Santos MCF, de Melo Campos JTA. J Rare Dis Res Treat. (2018) 3(2): 1-6 Journal of www.rarediseasesjournal.com Rare Diseases Research & Treatment Mini-review Open Access Congenital Generalized Lipodystrophy Josivan Gomes Lima1*, Marcel Catão Ferreira dos Santos1, Julliane Tamara Araújo de Melo Campos2 1Departamento de medicina clínica, disciplina de endocrinologia e metabologia. Hospital Universitário Onofre Lopes, Universidade Federal do Rio Grande do Norte (UFRN), Natal, RN, Brazil. 2Faculty of Health Sciences of Trairi, Federal University of Rio Grande do North (UFRN), Natal, RN, Brazil ABSTRACT Article Info Article Notes Congenital Generalized Lipodystrophy (CGL) is a rare and severe autosomal Received: April 02, 2018 recessive disease. Patients are defective in the storage of body fat and, Accepted: May 11, 2018 consequently, they deposit fat in ectopic tissues, mainly liver, and can develop cirrhosis. Insulin resistance is a typical finding, causing diabetes that require *Correspondence: high daily doses of insulin. In the state of Rio Grande do Norte, Brazil, we Dr. Josivan Gomes Lima, Departamento de medicina clínica, disciplina de endocrinologia e metabologia. Hospital have one of the largest cohorts of patients with CGL. In this article, we review Universitário Onofre Lopes, Universidade Federal do Rio pathophysiology, clinical picture and treatment of this disease. Grande do Norte (UFRN), Natal, RN, Brazil; Email: [email protected] © 2018 Lima JG. This article is distributed under the terms of Introduction the Creative Commons Attribution 4.0 International License. Type 2 diabetes is a world health problem, and usually results Keywords Lipodystrophy from excessive weight and increased visceral fat causing peripheral Berardinelli-Seip syndrome insulin resistance and an inability of the pancreas to release Diabetes insulin to compensate this resistance. Other less common types of Hypertriglyceridemia diabetes occur due to specific genetic mutations, like the Congenital Generalized Lipodystrophy (CGL), also known as Berardinelli-Seip TheCongenital altered Lipodystrophygenes play essential (BSCL). functions CGL is foran adipocyteautosomal formation, recessive lipiddisease production that is classified and proper into fourstorage types, inside based the on adipocyte.gene mutation. The mutations decrease adipose tissue with consequent deposition of fat in ectopic sites, causing fat liver, altered carbohydrate metabolism, severe insulin resistance with hyperinsulinemia and acromegaloid features, and dyslipidemia 1-3 . The CGL syndrome has around 500 cases reported in the, . Inworld. a descriptive In Brazil, instudy the Stateusing ofsecondary Rio Grande data, do Norte (RN), we have4 5 diagnosed, treated, and6. This followed indicates 54 casesa much in the past 20 years 7. we estimated a total of 103 patients in RN Triacylglycerolhigher prevalence formation than that reported and storage in the in literature lipid droplets (1: 1 million) The biosynthesis of triglycerides and phospho lipids (Figure 1A) starts with glycerol-3-phosphate acyltransferase (GPAT) acylating the glycerol-3-phosphate in position 1, forming 1-Acylglycerol- 3-phosphate (lysophosphatidic acid). It is followed by another acylation step at position two by the enzyme AGPAT (1-Acylglycerol- biosynthesis3-phosphate pathwayacyltransferase), of both triglycerides originating and 1,2-Diacylglycerol-3- phosphoglycerides. phosphate (phosphatidic acid). It is a key intermediate step in the. 4 presentThere are at 11 high isoforms levels of in AGPAT testis, enzymes, pancreas, encoded and, to bya lesserdifferent extent, genes in AGPAT1 and AGPAT2 are the most extensively studied. AGPAT1 is Page 1 of 6 Lima JG, Dos Santos MCF, de Melo Campos JTA. J Rare Dis Res Treat. (2018) 3(2): 1-6 Journal of Rare Diseases Research & Treatment Figure 1: Scheme of triglycerides synthesis according to CGL types. (A) Normal synthesis and storage of triacylglycerol (TAG) in the adipocyte. (B) Mutation ofAGPAT2 decreases TAG production (some is still synthesized under stimulation of other AGPATs). (C) Mutation of seipin gene decrease TAG synthesis and lipid droplet (LD) formation and fusion. (D) Caveolin-1 and Cavin-1 are required for the formation and stabilization of the caveolae. Mutation in CAV1 (type 3) or CAVIN1 (type 4) can cause loss of caveolae in the membrane. Nc, nucleus. ER, endoplasmic reticulum. Mc, mitochondria. *Lipin is a cytosolic enzyme anchored by seipin in the ER. followingadipose tissue steps, and the other cytosolic tissues enzyme like heart, phosphatidic placenta, brain, acid In the adipocytes, caveolae, which are specialized 50- lung, whereas AGPAT2 is abundant in fatty tissue. In the with100nm the membrane highest density invaginations, of caveolae account. The formation for 20% ofof lipid the plasma membrane area, making the13 adipocytes the cells triacylglycerolphosphatase (PAP or lipin) originates 1,2-diacylglycerol, alsoand theoriginate 1,2-diacylglycerol4 other phospholipids acyltransferase such as(DGAT) cardiolipin, forms droplets needs a membrane. The genes protein CAV1, CAV2, (Caveolin and CAV3 - the encode main phosphatidylinositol,. Phosphatidic and phosphatidylcholine. acid and diacylglycerol can component of caveolae14 membranes) and a cytoplasmic protein (Cavin-1) Those reactions occur in the adipocytes’ endoplasmic three forms of caveolin with similar structures (Caveolin-1, Caveolin-2, and Caveolin-3, respectively). Caveolin-1 8. and cardiacCaveolin-2 muscle are present in adipocytes, fibroblast, and reticulumThe product (ER), of the where gene BSCL2a progressive is a transmembrane accumulation protein of endothelial cells, and13, Caveolin-315 is present only in skeletal triglycerides causes the formation of small lipid droplets (LD) and the most studied. It is expressed in two different . Caveolin-1 is the most important called seipin that causes the fusion of small LD, originating plasma membrane to lipid droplet, being necessary to isoforms (1a and 1b). Caveolin-116 .translocates Lipid droplets from store the large LD. Seipin resides in the ER and concentrates at the9. junction with nascent LD, facilitating the lipid traffic between triglycerides after feeding and these molecules are lipid trafficking and metabolism ER and LD and the incorporation of triglycerides in LD hydrolyzed to fatty acid, and released during fasting; this 16 andSeipin morphology, may also act seipin as an is ERalso anchor essential to thefor adipogenesiscytosolic enzyme (via lipin 1. Besides being necessary for lipid droplet fusion, size,. mechanism17 may be regulated by Caveolin-1 . Caveolin-1 10, 11 autophagy . deficiency also increases susceptibility to cell death by interaction to lipin 1) and cellular triglyceride lipolysis 9, The gene CAVIN1 encodes a cytoplasmic protein asDeficiency shown by of studiesseipin doesin mesenchymal hamper the stemdifferentiation cells with ofBSCL2 pre- , that is adipocytes to12 adipocytes and affects the final maturation obligatory for the formation and stabilization of14, 16caveolae. other functions are to be determined. called caveolae associated protein 1 (Cavin-1) knocked out . Non-adipose tissues also express seipin, and Cavin-1 is expressed in adipocytes, muscle cells, and Page 2 of 6 Lima JG, Dos Santos MCF, de Melo Campos JTA. J Rare Dis Res Treat. (2018) 3(2): 1-6 Journal of Rare Diseases Research & Treatment other cells, and is also essential in the transmission of CGL Type 1. In 1999, Garg et al. described patients’ CAV1 gene 14, 18 caveolae-originatedCAVIN1 signalscauses the. Knockoutabsence of of caveolaethe in all bymutation this mutation on chromosome2, 19 9q34, and three yearsAGPAT2 later, tissues,causes a including lack of caveolae muscle in non-muscle cells, whereas the noneAgarwal or minimalet al. showed production AGPAT2 of astriacylglycerol the enzyme happensaffected knockout of 14 by the stimulus of .other Due toisoforms. mutation The of phenotypethis of and the signals of other pathways.. The lack of caveolae can affect regulation of lipolysis, fatty acid flux, triglyceride synthesis, Types of CGL pathophysiologyAGPAT2 knockout mice. is similar to that of humans with CGL type, confirming20, 21 the role of this enzyme in the CGL Type 2. cases,Based and on type detectable 2 has a moregenetic severely alterations, affected four phenotype. types are Magre et al. were the first to identify the3 described. Types 1 and 2 are responsible for over 95% of (mutationBSCL2 in the seipin gene (chromosome 11q13) been reported . Mutations (mostly nonsense) of the seipin gene Only one case 4of type 3 and around 30 cases of type 4 have ) produce a truncated protein and can affect lipid metabolism by different mechanisms: a) decrease in Figure 2: Hands of patients with CGL types 1 and 2. (A) and (B) Anterior and posterior views of hands of type 1 patients. Apparently normal hands, since there is still mechanical fat tissue. (C) and (D) Anterior and posterior views of hands of type 2 patients. The severity of the disease is greater, and the lack of fat is evident and easily noticeable. Page 3 of 6 Lima JG, Dos Santos MCF, de Melo Campos JTA. J Rare Dis Res Treat. (2018) 3(2): 1-6 Journal of Rare Diseases Research & Treatment a few years27 patients27. seipin stability; b) 11reduction in ability to bind lipin 1; and . Arterial hypertension occurs in one-third of triacylglycerolc) failure to oligomerize and small and lipid localize droplets, itself but exclusively large lipid to the ER membrane . Some cells are
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