Abhimanyu Garg

University of Texas Southwestern Medical Center, Dallas, Texas, United States

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Publications (161)1357.58 Total impact

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    ABSTRACT: Despite remarkable progress in identifying causal genes for many types of genetic lipodystrophies in the last decade, the molecular basis of many extremely rare lipodystrophy patients with distinctive phenotypes remains unclear. We conducted whole exome sequencing of the parents and probands from six pedigrees with neonatal onset of generalized loss of subcutaneous fat with additional distinctive phenotypic features and report de novo heterozygous null mutations, c.424C>T (p.Q142*) and c.479_480delTT (p.F160*), in CAV1 in a 7-year-old male and a 3-year-old female of European origin, respectively. Both the patients had generalized fat loss, thin mottled skin and progeroid features at birth. The male patient had cataracts requiring extraction at age 30 months and the female patient had pulmonary arterial hypertension. Dermal fibroblasts of the female patient revealed negligible CAV1 immunofluorescence staining compared to control but there were no differences in the number and morphology of caveolae upon electron microscopy examination. Based upon the similarities in the clinical features of these two patients, previous reports of CAV1 mutations in patients with lipodystrophies and pulmonary hypertension, and similar features seen in CAV1 null mice, we conclude that these variants are the most likely cause of one subtype of neonatal onset generalized lipodystrophy syndrome. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 04/2015; DOI:10.1002/ajmg.a.37115 · 2.05 Impact Factor
  • Iram Hussain, Zahid Ahmad, Abhimanyu Garg
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    ABSTRACT: Pseudohyponatremia has been reported in association with severe hypertriglyceridemia and hyperparaproteinemia, but its association with severe hypercholesterolemia is not well-known. We report a 43-year-old woman with refractory primary biliary cirrhosis who presented with asymptomatic hyponatremia (121 mmol/L; normal range: 135-145 mmol/L). She was ultimately found to have a total serum cholesterol level of 2415 mg/dL (normal range: 120-199 mg/dL) - secondary to accumulation of lipoprotein-X-causing pseudohyponatremia. The diagnosis was confirmed by measurement of serum osmolality (296 mOsm/kg H2O; normal range: 270-300 mOsm/kg H2O) and serum sodium by direct potentiometry (141 mmol/L). Furthermore, following 16 sessions of plasmapheresis over a 4-month period, there was marked lowering of serum cholesterol to 200 mg/dL and normalization of serum sodium (139 mmol/L) as measured by indirect potentiometry. This case shows that extreme hypercholesterolemia from elevation of lipoprotein-X particles in cholestasis can be a rare cause of pseudohyponatremia. It highlights the need to measure serum sodium with direct potentiometry in the setting of extreme hypercholesterolemia and consider this possibility before initiating treatment of hyponatremia. Published by Elsevier Inc.
    Journal of Clinical Lipidology 11/2014; 43(2). DOI:10.1016/j.jacl.2014.11.007 · 3.59 Impact Factor
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    ABSTRACT: Context: Sitosterolemia is an autosomal recessive disorder characterized by increased intestinal absorption of plant sterols. It is caused by mutations in genes encoding ATP-binding cassette, subfamily G5 (ABCG5) or G8 (ABCG8), and clinical features include elevated plant sterol levels, xanthomas and accelerated atherosclerosis. Although it was originally reported in patients with normolipemic xanthomas, patients with sitosterolemia also hyperabsorb cholesterol and serum cholesterol levels tend to be elevated. Objective: We report an infant with sitosterolemia who presented with severe hypercholesterolemia and intertriginous xanthomas. Case Report: A 15-month-old Korean girl presented with yellow dermal plaques over flexural areas including the wrist, neck, and gluteal folds, which were consistent with intertriginous xanthomas. The lesions were first noticed at 3 months of age when she was being exclusively breastfed. Her total cholesterol and low density lipoprotein-cholesterol (LDL-C) was 675 and 540 mg/dL, respectively. Low-fat/low-cholesterol diet and cholestyramine therapy were introduced. Unexpectedly, serum cholesterol level decreased dramatically, and normalized in 2 months. Cholestyramine was tapered off. The xanthomas also regressed and disappeared by 3 years of age. Gas chromatography-mass spectrometric analysis was performed with serum drawn at 3 years of age when her LDL-C was 118 mg/dL, which revealed striking elevation of sitosterol level at 19.36 mg/dL. Direct sequencing for ABCG5 revealed compound heterozygous null mutations c.904+1G>A (p.Met302Asnfs*82) and c.1336C>T(p.Arg446*). Conclusions: Our case suggests that sitosterolemia can present with severe hypercholesterolemia and intertriginous xanthomas. Sitosterolemia should be suspected when a patient with hypercholesterolemia shows unexpectedly good response to dietary modification or bile acid sequestrant therapy.
    The Journal of Clinical Endocrinology and Metabolism 05/2014; 99(5):jc20133274. DOI:10.1210/jc.2013-3274 · 6.31 Impact Factor
  • Journal of Clinical Lipidology 05/2014; 8(3):304–305. DOI:10.1016/j.jacl.2014.02.026 · 3.59 Impact Factor
  • Abhimanyu Garg, Chao Xing
    American Journal of Medical Genetics Part A 05/2014; 164(5). DOI:10.1002/ajmg.a.36449 · 2.05 Impact Factor
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    ABSTRACT: Type I hyperlipoproteinemia (T1HLP) is a rare, autosomal recessive disorder characterized by extreme hypertriglyceridemia that fails to respond to lipid-lowering agents, predisposing to frequent attacks of acute pancreatitis. Mutations in lipoprotein lipase (LPL), apolipoprotein CII (APOC2), lipase maturation factor 1 (LMF1), glycosyl-phosphatidylinositol anchored high-density lipoprotein-binding protein 1 (GPIHBP1), and apolipoprotein AV (APOA5) cause T1HLP, but we lack data on phenotypic variations among the different genetic subtypes. To study genotype-phenotype relationships among subtypes of T1HLP patients. Genetic screening for mutations in LPL, APOC2, GPIHBP1, LMF1, and APOA5. Tertiary referral center. Ten patients (7 female, 3 male) with chylomicronemia, serum triglyceride levels about 2000 mg/dL, and no secondary causes of hypertriglyceridemia. Genotyping and phenotypic features. Four patients harbored homozygous or compound heterozygous mutations in LPL, 3 had homozygous mutations in GPIHBP1, and 1 had a heterozygous APOA5 mutation. We failed to fully identify the genetic etiology in 2 cases: 1 had a heterozygous LPL mutation only and another did not have any mutations. We identified 2 interesting phenotypic features: the patient with heterozygous APOA5 mutation normalized triglyceride levels with weight loss and fish oil therapy, and all 7 female patients were anemic. Our data suggest the possibility of novel loci for T1HLP. We observed that heterozygous APOA5 mutation can cause T1HLP but such patients may unexpectedly respond to therapy, and females with T1HLP suffer from anemia. Further studies of larger cohorts may elucidate more phenotype-genotypes relationships among T1HLP subtypes.
    Journal of Clinical Lipidology 05/2014; 8(3):287-95. DOI:10.1016/j.jacl.2014.02.006 · 3.59 Impact Factor
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    ABSTRACT: In this study we examined the role of phosphatidic acid (PA) in hepatic glucose production (HGP) and development of hepatic insulin resistance in mice that lack AGPAT2. Liver LPA and PA levels were increased ~2-fold and ~5-fold respectively in male Agpat2-/- mice compared to WT mice. In the absence of AGPAT2, the liver can synthesize PAs by activating diacylglycerol kinase or phospholipase D, both of which were elevated in the livers of Agpat2-/- mice. We found that PAs C16:0/18:1 and C18:1/20:4 enhanced HGP in primary WT hepatocytes, an effect that was further enhanced in primary hepatocytes from Agpat2-/- mice. LPAs C16:0 and C18:1 failed to increase HGP in primary hepatocytes. The activation of HGP was accompanied by an upregulation of the key gluconeogenic enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. This activation was suppressed by insulin in the WT primary hepatocytes but not in the Agpat2-/- primary hepatocytes. Thus, the lack of normal insulin signaling in Agpat2-/- livers allows unrestricted PA-induced gluconeogenesis significantly contributing to the development of hyperglycemia in these mice.
    Journal of Biological Chemistry 01/2014; 289(8). DOI:10.1074/jbc.M113.530998 · 4.60 Impact Factor
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    ABSTRACT: Leptin is essential for energy homeostasis and regulation of food intake. Patients with congenital generalized lipodystrophy (CGL) due to mutations in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) and the CGL murine model Agpat2-/- mice, both, have severe insulin resistance, diabetes mellitus, hepatic steatosis and low plasma leptin levels. In this study, we show that continuous leptin treatment of Agpat2-/- mice for 28 days reduced plasma insulin and glucose levels and normalized hepatic steatosis and hypertriglyceridemia in Agpat2-/- mice. Leptin also partially, but significantly reversed the low plasma thyroxine and high corticosterone levels found in Agpat2-/- mice. Levels of carbohydrate response element binding protein (ChREBP) were reduced, whereas lipogenic gene expression were increased in the livers of Agpat2-/- mice, suggesting that deregulated ChREBP contributed to the development of fatty livers in these mice and that this transcription factor is a target of leptins beneficial metabolic action. Leptin administration did not change hepatic fatty acid oxidation enzymes mRNA levels in Agpat2-/- mice. The selective deletion of leptin receptors only in hepatocytes did not prevent the positive metabolic actions of leptin in Agpat2-/- mice, supporting the previous studies suggesting that the majority of metabolic actions of leptin are dependent on its action in non-hepatocyte cells and/or the central nervous system.
    The Journal of Lipid Research 11/2013; 55(2). DOI:10.1194/jlr.M045799 · 4.73 Impact Factor
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    ABSTRACT: There is some evidence that bariatric surgery patients who undergo the purely restrictive procedures, such as the gastric banding (GB) or the vertical banded gastroplasty surgery, do not meet the dietary reference intakes for several nutrients. Whether dietary counseling improves micronutrient and macronutrient intakes was examined in GB surgery patients. Twenty-three GB surgery patients received dietary and behavioral counseling for 12 weeks to limit energy intake and improve nutrient intakes. Food intake was assessed by 3-day food record at baseline and 6 and 12 weeks. Postintervention data were available in 21 patients. At baseline, more than 50% of the subjects reported inadequate dietary intakes of 13 nutrients but overconsumption of sodium and percent energy from saturated and trans-fatty acids. Mixed-effects model for repeated measures revealed a significant reduction in energy (P = 0.0007), absolute protein (P = 0.04), cholesterol (P = 0.045), and potassium (P = 0.01) intake and an increase in vitamin K (P = 0.03) intake and percent energy from protein (P = 0.005) during the 12 weeks. The McNemar test showed a reduction in the proportion of the subjects with an inadequate intake of vitamin K (P = 0.008) but an increase in the proportion of the subjects with an inadequate intake of thiamin (P = 0.03) at 12 weeks. The proportion of the subjects who did not meet the nutrient requirements for the remaining 27 nutrients was generally high and remained unchanged. Dietary intervention improved the intake of some nutrients in the GB surgery patients. However, most nutrient intake requirements remained unmet by many subjects. These results indicate that nutritional counseling beyond 12 weeks is warranted in GB surgery patients to improve their dietary nutrient intakes.
    Journal of Investigative Medicine 10/2013; DOI:10.231/JIM.0000000000000002 · 1.50 Impact Factor
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    ABSTRACT: Generalized lipodystrophy is a rare disorder characterized by marked loss of adipose tissue with reduced triglyceride storage capacity, leading to a severe form of metabolic syndrome including hypertriglyceridemia, insulin resistance, type 2 diabetes mellitus, and hepatic steatosis. Recent echocardiographic studies suggest that concentric left ventricular (LV) hypertrophy is another characteristic feature of this syndrome, but the mechanism remains unknown. It has recently been hypothesized that the LV hypertrophy could be an extreme clinical example of "lipotoxic cardiomyopathy": excessive myocyte accumulation of triglyceride leading to adverse hypertrophic signaling. To test this hypothesis, the first cardiac magnetic resonance study of patients with generalized lipodystrophy was performed, using magnetic resonance imaging and localized proton spectroscopy to detect excessive triglyceride content in the hypertrophied myocytes. Six patients with generalized lipodystrophy and 6 healthy controls matched for age, gender, and body mass index were studied. As hypothesized, myocardial triglyceride content was threefold higher in patients than controls: 0.6 ± 0.2% versus 0.2 ± 0.1% (p = 0.004). The presence of pericardial fat was also found, representing a previously undescribed adipose depot in generalized lipodystrophy. Patients with generalized lipodystrophy, compared with controls, also had a striking degree of concentric LV hypertrophy, independent of blood pressure: LV mass index 101.0 ± 18.3 versus 69.0 ± 17.7 g/m(2), respectively (p = 0.02), and LV concentricity 1.3 ± 0.3 versus 0.99 ± 0.1 g/ml, respectively (p = 0.04). In conclusion, these findings advance the lipotoxicity hypothesis as a putative underlying mechanism for the dramatic concentric LV hypertrophy found in generalized lipodystrophy.
    The American journal of cardiology 06/2013; 112(7). DOI:10.1016/j.amjcard.2013.05.036 · 3.43 Impact Factor
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    ABSTRACT: Introduction:Familial partial lipodystrophy, Dunnigan variety (FPLD), an autosomal dominant disorder caused by LMNA mutations, is characterized by fat loss from the extremities. However, it is unclear whether these patients appear muscular because of a lack of subcutaneous fat or have an actual increase in muscle mass. Therefore, we compared muscle mass and volume of selected muscles in women with FPLD and control subjects using dual-emission x-ray absorptiometry (DXA) and magnetic resonance imaging (MRI).Methods:Whole-body axial MRI and DXA scans were obtained on 39 women, aged 18 to 65 years, with FPLD and 17 healthy women matched for body mass index and age (group 1). Volumes of muscles in both the thighs, calves, and psoas were calculated from MRI scans and lean mass in extremities were calculated from DXA. In addition, abdominal MRI and DXA scans were analyzed from 129 healthy, frequency-matched women (group 2). Comparisons between women with FPLD and control subjects were made using ANOVA, adjusting for height, body mass index, and age.Results:Patients with FPLD, compared with control subjects had significantly greater volumes of the thigh muscles, (6358 ± 1491 vs 5198 ± 716 mL, P = .002), calf muscles (3133 ± 713 vs 2397 ± 335 mL; P < .001), and psoas muscles (210 ± 51 vs 175 ± 34 [group 1] and 165 ± 38 mL [group 2], P < .001). Patients with FPLD also had significantly increased arm and leg lean masses when measured by DXA (P < .001). Insulin sensitivity, assessed by insulin tolerance tests, was negatively correlated to the calf volume.Conclusions:Female patients with FPLD have increased skeletal muscle volume and mass compared with those of normal women.
    The Journal of Clinical Endocrinology and Metabolism 06/2013; 98(8). DOI:10.1210/jc.2013-1297 · 6.31 Impact Factor
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    ABSTRACT: OBJECTIVE: Hepatic steatosis is a common complication in patients with lipodystrophies and can lead to cirrhosis. There is no proven effective therapy for hepatic steatosis, but cholic acid (CA), a farnesoid X receptor agonist, has previously been shown to reduce hepatic triglyceride (TG) content in mice and serum triglycerides in humans. Our objective was to assess clinical efficacy and tolerability of CA therapy in patients with lipodystrophy and hepatic steatosis. DESIGN: A randomized, double-blind, placebo-controlled, crossover study. METHODS: Eighteen patients with genetic or autoimmune lipodystrophies, and elevated hepatic TG content participated in the study. The intervention was CA (15 mg/kg/day) compared with placebo for a period of 6 months each. Hepatic TG content, the primary outcome variable, was measured with 1H magnetic resonance spectroscopy at baseline and at 3 and 6 months during each study period. Levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT) and TG were secondary end-points of the study. RESULTS: Compared to placebo, CA did not reduce hepatic TG content [median (interquartile range) 14.8% (9.4-19.0%) vs. 15.9% (10.5-26.5%), respectively; p = 0.42] or serum TG [340 mg/dL (233 - 433 mg/dL) vs. 390 mg/dL (233 - 595 mg/dL) respectively; p=0.45]. CA therapy also did not change AST, ALT or GGT levels. Two patients developed diarrhea and excessive flatus while taking CA and these symptoms resolved after reducing the dose of CA. CONCLUSION: CA was well tolerated but did not reduce hepatic TG content in patients with lipodystrophy.
    European Journal of Endocrinology 02/2013; DOI:10.1530/EJE-12-0969 · 3.69 Impact Factor
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    ABSTRACT: BACKGROUND: -Autosomal dominant hypercholesterolemia (ADH), characterized by elevated plasma levels of low density lipoprotein-cholesterol (LDL-C), is caused by variants in at least three different genes: LDL receptor (LDLR), apolipoprotein B-100 (APOB), and proprotein convertase subtilisin-like kexin type 9 (PCSK9). There is paucity of data about the molecular basis of ADH among ethnic groups other than those of European or Japanese descent. Here, we examined the molecular basis of ADH in a multi-ethnic patient cohort from lipid clinics in a large urban U.S. city. METHODS AND RESULTS: -A total of 38 males and 53 females, age 22 to 76 years, met modified Simon-Broome criteria for ADH and were screened for mutations in the exons and consensus splice sites of LDLR, and in selected exons of APOB and PCSK9. Deletions and duplications of LDLR exons were detected with multiplex ligation-dependent probe amplification. Heterozygous variants in LDLR were identified in 30 patients and in APOB in one patient. The remaining 60 patients (65%) had "unexplained ADH." A higher proportion of African Americans (77%) than either non-Hispanic whites (57%) or Hispanics (53%) had "unexplained ADH." As compared to patients with LDLR variants, those with "unexplained ADH" had lower levels of LDL-C (292 ± 47 vs 239 ± 42 mg/dL, respectively; p < 0.0001) and higher levels of HDL-cholesterol (45 ± 12 vs 54 ± 13 mg/dL, respectively, p = 0.003). CONCLUSIONS: -Our findings suggest that additional loci may contribute to ADH, especially in understudied populations such as African Americans.
    Circulation Cardiovascular Genetics 10/2012; 5(6). DOI:10.1161/CIRCGENETICS.112.963587 · 5.34 Impact Factor
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    ABSTRACT: Ahmad Z, Phadke SR, Arch E, Glass J, Agarwal AK, Garg A. Homozygous null mutations in ZMPSTE24 in restrictive dermopathy: evidence of genetic heterogeneity.Restrictive dermopathy (RD) results in stillbirth or early neonatal death. RD is characterized by prematurity, intrauterine growth retardation, fixed facial expression, micrognathia, mouth in the ‘o’ position, rigid and tense skin with erosions and denudations and multiple joint contractures. Nearly all 25 previously reported neonates with RD had homozygous or compound heterozygous null mutations in the ZMPSTE24 gene. Here, we report three new cases of RD; all died within 3 weeks of birth. One of them had a previously reported homozygous c.1085dupT (p.Leu362PhefsX19) mutation, the second case had a novel homozygous c.1020G>A (p.Trp340X) null mutation in ZMPSTE24, but the third case, a stillborn with features of RD except for the presence of tapering rather than rounded, bulbous digits, harbored no disease‐causing mutations in LMNA or ZMPSTE24. In the newborn with a novel ZMPSTE24 mutation, unique features included butterfly‐shaped thoracic 5 vertebra and the bulbous appearance of the distal clavicles. Skin biopsies from both the stillborn fetus and the newborn with c.1020G>A ZMPSTE24 mutation showed absence of elastic fibers throughout the dermis. This report provides evidence of genetic heterogeneity among RD and concludes that there may be an additional locus for RD which remains to be identified.
    Clinical Genetics 01/2012; 81(2). · 3.65 Impact Factor
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    ABSTRACT: Leptin replacement therapy improves metabolic complications in patients with lipodystrophy and severe hypoleptinemia (SH), but whether the response is related to the degree of hypoleptinemia remains unclear. The aim of the study was to compare efficacy of leptin therapy in familial partial lipodystrophy, Dunnigan variety (FPLD) patients with SH (serum leptin<7th percentile of normal) vs. those with moderate hypoleptinemia (MH; serum leptin in 7th to 20th percentiles). DESIGN, SETTING, and We conducted an open-label, parallel group, observational study in 14 SH (mean±sd, serum leptin, 1.9±1.1 ng/ml) and 10 MH (serum leptin, 5.3±1.0 ng/ml) women with FPLD. Patients received 0.08 mg/kg·d of metreleptin by twice daily sc injections for 6 months. The primary outcome variable was change in fasting serum triglycerides. Other secondary variables were fasting plasma glucose and insulin, insulin sensitivity, hemoglobin A1c, and hepatic triglyceride content. Median fasting serum triglycerides decreased from 228 to 183 mg/dl in the SH group (P=0.04) and from 423 to 339 mg/dl in the MH group (P=0.02), but with no difference between the groups (P value for interaction=0.96). Hepatic triglyceride levels similarly declined significantly from 8.8 to 4.9% in the SH group and from 23.7 to 9.2% in the MH group (P value for interaction=0.9). Loss of body weight and body fat occurred in both groups. Fasting glucose, insulin, glucose tolerance, and hemoglobin A1c levels did not change. K value on insulin tolerance test improved slightly in the SH group (0.98 to 1.24%; P=0.01), but not in the MH group (1.1 to 1.27%; P=0.4). Metreleptin replacement therapy is equally effective in FPLD patients with both SH and MH in reducing serum and hepatic triglyceride levels, but did not improve hyperglycemia.
    The Journal of Clinical Endocrinology and Metabolism 12/2011; 97(3):785-92. DOI:10.1210/jc.2011-2229 · 6.31 Impact Factor
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    ABSTRACT: Loss-of-function mutations in 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) 2 in humans and mice result in loss of both the white and brown adipose tissues from birth. AGPAT2 generates precursors for the synthesis of glycerophospholipids and triacylglycerols. Loss of adipose tissue, or lipodystrophy, results in hyperinsulinemia, diabetes mellitus, and severe hepatic steatosis. Here, we analyzed biochemical properties of human AGPAT2 and its close homolog, AGPAT1, and we studied their role in liver by transducing their expression via recombinant adenoviruses in Agpat2−/− mice. The in vitro substrate specificities of AGPAT1 and AGPAT2 are quite similar for lysophosphatidic acid and acyl-CoA. Protein homology modeling of both the AGPATs with glycerol-3-phosphate acyltransferase 1 (GPAT1) revealed that they have similar tertiary protein structure, which is consistent with their similar substrate specificities. When co-expressed, both isoforms co-localize to the endoplasmic reticulum. Despite such similarities, restoring AGPAT activity in liver by overexpression of either AGPAT1 or AGPAT2 in Agpat2−/− mice failed to ameliorate the hepatic steatosis. From these studies, we suggest that the role of AGPAT1 or AGPAT2 in liver lipogenesis is minimal and that accumulation of liver fat is primarily a consequence of insulin resistance and loss of adipose tissue in Agpat2−/− mice.
    Journal of Biological Chemistry 10/2011; 286(43):37676-37691. · 4.60 Impact Factor
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    ABSTRACT: Lipoprotein lipase (LPL) is a hydrolase that cleaves circulating triglycerides to release fatty acids to the surrounding tissues. The enzyme is synthesized in parenchymal cells and is transported to its site of action on the capillary endothelium by glycophosphatidylinositol (GPI)-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). Inactivating mutations in LPL; in its cofactor, apolipoprotein (Apo) C2; or in GPIHBP1 cause severe hypertriglyceridemia. Here we describe an individual with complete deficiency of GPIHBP1. The proband was an Asian Indian boy who had severe chylomicronemia at 2 months of age. Array-based copy-number analysis of his genomic DNA revealed homozygosity for a 17.5-kb deletion that included GPIHBP1. A 44-year-old aunt with a history of hypertriglyceridemia and pancreatitis was also homozygous for the deletion. A bolus of intravenously administered heparin caused a rapid increase in circulating LPL and decreased plasma triglyceride levels in control individuals but not in two GPIHBP1-deficient patients. Thus, short-term treatment with heparin failed to attenuate the hypertriglyceridemia in patients with GPIHBP1 deficiency. The increasing resolution of copy number microarrays and their widespread adoption for routine cytogenetic analysis is likely to reveal a greater role for submicroscopic deletions in Mendelian conditions. We describe the first neonate with complete GPIHBP1 deficiency due to homozygosity for a deletion of GPIHBP1. Electronic supplementary material The online version of this article (doi:10.1007/s10545-011-9406-5) contains supplementary material, which is available to authorized users.
    Journal of Inherited Metabolic Disease 10/2011; 35(3):531-40. DOI:10.1007/s10545-011-9406-5 · 4.14 Impact Factor
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    ABSTRACT: Type 1 hyperlipoproteinemia (T1HLP) in childhood is most often due to genetic deficiency of lipoprotein lipase (LPL) or other related proteins. The aim was to report a case of marked hypertriglyceridemia and recurrent acute pancreatitis due to the presence of LPL autoantibody in a young girl who was subsequently diagnosed with Sjögren's syndrome. A 9-yr-old African-American girl presented with acute pancreatitis and serum triglycerides of 4784 mg/dl. Strict restriction of dietary fat reduced serum triglycerides, but she continued to experience recurrent pancreatitis. Approximately 18 months thereafter, she developed transient pauciarticular arthritis with elevated serum antinuclear antibody (>1:1280). Minor salivary gland biopsy revealed chronic sialadenitis with a dense periductal lymphocytic aggregate suggestive of Sjögren's syndrome. Genomic DNA was analyzed for LPL, GPIHBP1, APOA5, APOC2, and LMF1. Immunoblotting was performed to detect serum LPL autoantibody. The patient had no disease-causing variants in LPL, GPIHBP1, APOA5, APOC2, or LMF1. Immunoblotting revealed serum LPL antibody. The patient responded to immunosuppressive therapy for Sjögren's syndrome with resolution of hypertriglyceridemia. Unexplained T1HLP in childhood could be secondary to LPL deficiency induced by autoantibodies. Therefore, diagnosis of autoimmune T1HLP should be entertained if clinical features are suggestive of an autoimmune process.
    The Journal of Clinical Endocrinology and Metabolism 08/2011; 96(11):3302-7. DOI:10.1210/jc.2011-1113 · 6.31 Impact Factor
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    ABSTRACT: Loss-of-function mutations in 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) 2 in humans and mice result in loss of both the white and brown adipose tissues from birth. AGPAT2 generates precursors for the synthesis of glycerophospholipids and triacylglycerols. Loss of adipose tissue, or lipodystrophy, results in hyperinsulinemia, diabetes mellitus, and severe hepatic steatosis. Here, we analyzed biochemical properties of human AGPAT2 and its close homolog, AGPAT1, and we studied their role in liver by transducing their expression via recombinant adenoviruses in Agpat2(-/-) mice. The in vitro substrate specificities of AGPAT1 and AGPAT2 are quite similar for lysophosphatidic acid and acyl-CoA. Protein homology modeling of both the AGPATs with glycerol-3-phosphate acyltransferase 1 (GPAT1) revealed that they have similar tertiary protein structure, which is consistent with their similar substrate specificities. When co-expressed, both isoforms co-localize to the endoplasmic reticulum. Despite such similarities, restoring AGPAT activity in liver by overexpression of either AGPAT1 or AGPAT2 in Agpat2(-/-) mice failed to ameliorate the hepatic steatosis. From these studies, we suggest that the role of AGPAT1 or AGPAT2 in liver lipogenesis is minimal and that accumulation of liver fat is primarily a consequence of insulin resistance and loss of adipose tissue in Agpat2(-/-) mice.
    Journal of Biological Chemistry 08/2011; 286(43):37676-91. DOI:10.1074/jbc.M111.250449 · 4.60 Impact Factor
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    ABSTRACT: Loss-of-function mutations in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) in humans and mice result in loss of both the white and brown adipose tissue from birth. AGPAT2 generates precursors for the synthesis of glycerophospholipids and triacylglycerols. Loss of adipose tissue or lipodystrophy results in hyperinsulinemia, diabetes mellitus and severe hepatic steatosis. Here, we analyzed biochemical properties of human AGPAT2 and its close homolog, AGPAT1, and studied their role in liver by transducing their expression via recombinant adenoviruses in Agpat2-/- mice. The in-vitro substrate specificities of AGPAT1 and AGPAT2 are quite similar for lysophosphatidic acid and acyl-CoA. Protein homology modeling of both the AGPATs with glycerol-3-phosphate acyltransferase 1 (GPAT1) revealed that they have similar tertiary protein structure, which is consistent with their similar substrate specificities. When co-expressed, both isoforms co-localize to the endoplasmic reticulum. Despite such similarities, restoring AGPAT activity in liver by over expression of either AGPAT1 or AGPAT2 in Agpat2-/- mice failed to ameliorate the hepatic steatosis. From these studies we suggest that the role of AGPAT1 or AGPAT2 in liver lipogenesis is minimal and that accumulation of liver fat is primarily a consequence of insulin resistance and loss of adipose tissue in Agpat2-/- mice.
    Journal of Biological Chemistry 08/2011; · 4.60 Impact Factor

Publication Stats

11k Citations
1,357.58 Total Impact Points

Institutions

  • 1988–2015
    • University of Texas Southwestern Medical Center
      • • Division of Nutrition and Metabolic Diseases
      • • Department of Internal Medicine
      • • Division of General Internal Medicine
      • • Center for Human Nutrition
      Dallas, Texas, United States
  • 2013
    • Texas Christian University
      • Department of Kinesiology
      Fort Worth, Texas, United States
  • 2011
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 2002–2011
    • University of Texas at Dallas
      Richardson, Texas, United States
    • National Institutes of Health
      • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      Bethesda, MD, United States
  • 2005
    • Stanford University
      Palo Alto, California, United States
  • 1997
    • All India Institute of Medical Sciences
      • Department of Medicine
      New Delhi, NCT, India