Alternative titles; symbols
HGNC Approved Gene Symbol: LIPE
SNOMEDCT: 1197751007;
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38): 19:42,401,514-42,427,388 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.2 | Lipodystrophy, familial partial, type 6 | 615980 | Autosomal recessive | 3 |
Hormone-sensitive lipase (HSL; EC 3.1.1.3) has a vital role in the mobilization of free fatty acids from adipose tissue by controlling the rate of lipolysis of the stored triglycerides. HSL regulates energy homeostasis by catalyzing the rate-limiting step in adipose tissue lipolysis. Like glycogen phosphorylase, the corresponding enzyme in carbohydrate metabolism, HSL is under acute neuronal and hormonal control. In both cases activation by catecholamines occurs through the cAMP-mediated phosphorylation of a single serine residue. The dephosphorylation of HSL by insulin is responsible for the antilipolytic effect of this hormone, one of its most important actions (summary by Holm et al., 1988).
Holm et al. (1988) cloned the gene for hormone-sensitive lipase from the rat adipocyte and found that the 757-amino acid sequence predicted by the cDNA showed no homology with any other known lipase or protein. The activity-controlling phosphorylation site was localized to serine-563 in a markedly hydrophilic domain, and a lipid-binding consensus site was tentatively identified.
Li et al. (1994) found that the Hsl mouse protein shares 94% sequence identity with the previously determined rat sequence and 85% identity with the human sequence. Despite the high degree of similarity, the 3 species diverge significantly for a stretch of 16 amino acid residues upstream of the phosphorylation site.
Holst et al. (1996) cloned and expressed a testicular isoform of HSL that has additional amino acids at the N terminus. As a result, rat and human testicular isoforms consist of 1,068 and 1,076 amino acids, respectively, compared to the 768 and 775 amino acids, respectively, of the adipocyte isoform. Holst et al. (1996) isolated a novel exon of 1.2 kb encoding the human testis-specific amino acids and mapped it to the HSL gene, 16 kb upstream of the exons encoding adipocyte HSL. A 3.3-kb transcript was detected in mammary gland, adrenal gland, adipose tissue and muscle, and both a 3.3- and 3.9-kb transcript were found in testis. No significant similarity with other known proteins was found for the testis-specific sequence. They used immunocytochemistry to localize HSL to elongated spermatids and spermatozoa; HSL was not detected in interstitial cells.
By Southern analysis of DNA from human-rodent somatic cell hybrids, Holm et al. (1988) mapped the human LIPE gene to chromosome 19cen-q13.3. By hybridization studies using a panel of somatic cell hybrids with subchromosomal segments of 19q, Schonk et al. (1990) localized the LIPE gene to 19q13.1. By fluorescence in situ hybridization, Levitt et al. (1995) mapped the gene to 19q13.1-q13.2.
Wang et al. (1994) demonstrated that the mouse Lipe gene is on proximal chromosome 7. They found that mouse Lipe gene is distinct from the Tub and Ad loci, which are associated with obesity in the mouse.
Because hormone-sensitive lipase is a key enzyme in overall energy homeostasis, Holm et al. (1988) suggested that variations in its expression or structure might be related to the development of obesity as well as to lipodystrophy syndromes (e.g., 151660) and lipomatosis (151800). Lipomatosis is characterized by formation of lipomas that are defective in adrenergic-stimulated lipolysis.
Using whole-genome sequencing to identify genes involved in high-altitude adaptation in 2 ethnically distinct groups of Ethiopian highlanders living at 3,500 meters above sea level on Bale Plateau or Chennek field in Ethiopia, Udpa et al. (2014) identified regions with significant loss of diversity, including a region on chromosome 19 that contains 8 genes, including CIC (612082), LIPE, and PAFAH1B3 (603074). The authors evaluated the roles of these genes in hypoxia tolerance by using small interfering RNA in Drosophila. Knockdown of Cic, Hsl, or Pafaha, the fly orthologs of CIC, LIPE, and PAFAH1B3, respectively, resulted in increased tolerance and survival in hypoxic environments. Udpa et al. (2014) concluded that these genes may encode evolutionarily conserved proteins involved in hypoxia tolerance.
Albert et al. (2014) sequenced 12 lipolytic-pathway genes in 24 Old Order Amish individuals whose fasting serum triglyceride levels were at the extremes of the distribution, and detected a 19-bp deletion in the LIPE gene (151750.0001) in an individual whose triglyceride level was at the upper extreme. Genotyping for the LIPE deletion in 2,738 participants in the Amish Complex Disease Research Program identified 1 individual who was homozygous for the deletion ('DD' genotype) and 140 heterozygotes. The homozygous proband had 3 sibs who were also homozygous for the deletion, and all exhibited impaired lipolysis and showed evidence for redistribution of body fat as well as altered metabolic traits, including systemic insulin resistance and diabetes (FPLD6; 615980). Carriers of the deletion had an increased risk of metabolic dysfunction.
In an Italian sister and brother from a consanguineous family with a late-onset form of partial lipodystrophy, originally reported by Carboni et al. (2014), Farhan et al. (2014) performed genomewide autozygosity mapping and whole-exome sequencing, and identified a frameshift mutation in the LIPE gene (151750.0002) that segregated with disease in the family. The mutation was not found in the NCBI dbSNP, 1000 Genomes Project, Human Gene Mutation, or Exome Variant Server databases, or in in-house control exomes.
In 3 affected sibs from a consanguineous Israeli Arab family with multiple symmetric lipomatosis, partial lipodystrophy, and myopathy, Zolotov et al. (2017) identified homozygosity for a nonsense mutation in the LIPE gene (E1035X; 151750.0003).
HSL is known to mediate the hydrolysis not only of triacylglycerol stored in adipose tissue but also of cholesterol esters in the adrenals, ovaries, testes, and macrophages. To elucidate its precise role in the development of obesity and steroidogenesis, Osuga et al. (2000) generated HSL knockout mice by homologous recombination in embryonic stem cells. Mice homozygous for the mutant allele were superficially normal except that the males were sterile due to oligospermia. The homozygous null mice did not have hypogonadism or adrenal insufficiency. Instead, the testes completely lacked neutral cholesterol ester hydrolase (NCEH) activities and contained increased amounts of cholesterol ester. Many epithelial cells in the seminiferous tubules were vacuolated. NCEH activities were completely absent from both brown adipose tissue (BAT) and white adipose tissue (WAT) in homozygous null mice. Consistently, adipocytes were significantly enlarged in the BAT (5-fold) and, to a lesser extent, in the WAT (2-fold), supporting the concept that the hydrolysis of triacylglycerol was, at least in part, impaired in homozygous null mice. The BAT mass was increased by 1.65-fold, but the WAT mass remained unchanged. Discrepancy of the size differences between cell and tissue suggested the heterogeneity of adipocytes. Despite these morphologic changes, homozygous null mice were neither obese nor cold sensitive. Furthermore, WAT from homozygous null mice retained 40% of triacylglycerol lipase activities compared with wildtype WAT. Osuga et al. (2000) concluded that HSL is required for spermatogenesis but is not the only enzyme that mediates the hydrolysis of triacylglycerol stored in adipocytes.
Das et al. (2011) showed that inhibition of lipolysis through genetic ablation of adipose triglyceride lipase (ATGL; 609059) or Hsl ameliorates certain features of cancer-associated cachexia. In wildtype C57BL/6 mice, the injection of Lewis lung carcinoma or B16 melanoma cells causes tumor growth, loss of white adipose tissue, and a marked reduction of gastrocnemius muscle. In contrast, Atgl-deficient mice with tumors resisted increased white adipose tissue lipolysis, myocyte apoptosis, and proteasomal muscle degradation and maintained normal adipose and gastrocnemius muscle mass. Hsl-deficient mice with tumors were also protected, although to a lesser degree. Das et al. (2011) concluded that functional lipolysis is essential in the pathogenesis of cancer-associated cachexia.
In 4 sibs from an Old Order Amish family with familial partial lipodystrophy type 6 (FPLD6; 615980), Albert et al. (2014) identified homozygosity for a 19-bp deletion (c.2300_2318del) in exon 9 of the LIPE gene, causing a frameshift predicted to result in a premature termination codon (Val767GlyfsTer102). These 4 individuals had dyslipidemia, hepatic steatosis, systemic insulin resistance, type 2 diabetes, and evidence for redistribution of body fat. Evaluation of the 4 homozygous sibs as well as 3 heterozygous and 3 noncarrier sibs showed that carriers of the deletion had higher triglyceride and insulin levels and lower HDL cholesterol and serum adiponectin (ADPN; 605441) levels than did noncarriers. Among 2,738 participants in the Amish Complex Disease Research Program, there were 140 heterozygous carriers of the deletion, giving a 5.1% carrier rate among the Amish compared to 0.2% among non-Amish persons of European descent. Association analysis showed that heterozygous carriers had an increased risk of dyslipidemia, with elevated triglycerides and reduced levels of HDL cholesterol, hepatic steatosis, and systemic insulin resistance, as well as an increased risk of type 2 diabetes (T2D; 125853) that was 1.8 times that of noncarriers. QT-PCR analysis of extracts of abdominal subcutaneous adipose tissue showed that homozygotes had LIPE mRNA levels that were approximately 30% of those of controls, whereas heterozygotes had levels similar to those of controls. Western blot analysis of the adipose tissue extracts showed no detectable LIPE protein in homozygotes, with an approximately 50% reduction in heterozygotes compared to controls. Examination of adipose tissue from 2 of the DD sibs revealed small adipocytes, impaired lipolysis, insulin resistance, and inflammation. In addition, transcription factors responsive to PPARG (601487) and downstream target genes were downregulated in DD adipose tissue, altering the regulation of pathways influencing adipogenesis, insulin sensitivity, and lipid metabolism.
In an Italian sister and brother from a consanguineous family with familial partial lipodystrophy type 6 (FPLD6; 615980), originally reported by Carboni et al. (2014), Farhan et al. (2014) identified homozygosity for a 2-bp insertion in the LIPE gene. Farhan et al. (2014) referred to the mutation as an indel. The mutation caused a frameshift within the hormone-sensitive lipase domain predicted to result in a premature termination codon (Ala507fsTer563) with an approximately 50% loss of the original polypeptide. The mutation segregated with disease in the family and was not found in the NCBI dbSNP, 1000 Genomes Project, Human Gene Mutation, or Exome Variant Server databases, or in in-house control exomes. Both sibs had a late-onset form of partial lipodystrophy with elevated levels of creatine kinase. The sister exhibited mild proximal muscle weakness and dystrophic changes on muscle biopsy, whereas her brother had normal strength.
In 3 affected sibs from a consanguineous Israeli Arab family with multiple symmetric lipomatosis, partial lipodystrophy, and myopathy (FPLD6; 615980), Zolotov et al. (2017) identified homozygosity for a c.3103G-T transversion (c.3103G-T, NM_005357.3) in the LIPE gene, resulting in a glu1035-to-ter (E1035X) substitution. The mutation segregated fully with disease in the family.
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., Breyer, R. J., III, Ryan, A. S., McLenithan, J. C., Shuldiner, A. R., Sztalryd, C., Damcott, C. M. Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes. New Eng. J. Med. 370: 2307-2315, 2014. [PubMed: 24848981] [Full Text: https://doi.org/10.1056/NEJMoa1315496]
Carboni, N., Brancati, F., Cocco, E., Solla, E., D'Apice, M. R., Mateddu, A., McIntyre, A., Fadda, E., Mura, M., Lattanzi, G., Piras, R., Maioli, M. A., Marrosu, G., Novelli, G., Marrosu, M. G., Hegele, R. A. Partial lipodystrophy associated with muscular dystrophy of unknown genetic origin. Muscle Nerve 49: 928-930, 2014. [PubMed: 24375490] [Full Text: https://doi.org/10.1002/mus.24157]
Das, S. K., Eder, S., Schauer, S., Diwoky, C., Temmel, H., Guertl, B., Gorkiewicz, G., Tamilarasan, K. P., Kumari, P., Trauner, M., Zimmermann, R., Vesely, P., Haemmerle, G., Zechner, R., Hoefler, G. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 333: 233-238, 2011. Note: Erratum: Science 333: 1576 only, 2011. [PubMed: 21680814] [Full Text: https://doi.org/10.1126/science.1198973]
Farhan, S. M. K., 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 late-onset familial partial lipodystrophy. Canad. J. Cardiol. 30: 1649-1654, 2014. [PubMed: 25475467] [Full Text: https://doi.org/10.1016/j.cjca.2014.09.007]
Holm, C., Kirchgessner, T. G., Svenson, K. L., Fredrikson, G., Nilsson, S., Miller, C. G., Shively, J. E., Heinzmann, C., Sparkes, R. S., Mohandas, T., Lusis, A. J., Belfrage, P., Schotz, M. C. Hormone-sensitive lipase: sequence, expression, and chromosomal localization to 19cent-q13.3. Science 241: 1503-1506, 1988. [PubMed: 3420405] [Full Text: https://doi.org/10.1126/science.3420405]
Holst, L. S., Langin, D., Mulder, H., Laurell, H., Grober, J., Bergh, A., Mohrenweiser, H. W., Edgren, G., Holm, C. Molecular cloning, genomic organization, and expression of a testicular isoform of hormone-sensitive lipase. Genomics 35: 441-447, 1996. [PubMed: 8812477] [Full Text: https://doi.org/10.1006/geno.1996.0383]
Levitt, R. C., Liu, Z., Nouri, N., Meyers, D. A., Brandriff, B., Mohrenweiser, H. M. Mapping of the gene for hormone sensitive lipase (LIPE) to chromosome 19q13.1-q13.2. Cytogenet. Cell Genet. 69: 211-214, 1995. [PubMed: 7698015] [Full Text: https://doi.org/10.1159/000133966]
Li, Z., Sumida, M., Birchbauer, A., Schotz, M. C., Reue, K. Isolation and characterization of the gene for mouse hormone-sensitive lipase. Genomics 24: 259-265, 1994. [PubMed: 7698747] [Full Text: https://doi.org/10.1006/geno.1994.1614]
Osuga, J., Ishibashi, S., Oka, T., Yagyu, H., Tozawa, R., Fujimoto, A., Shionoiri, F., Yahagi, N., Kraemer, F. B., Tsutsumi, O., Yamada, N. Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity. Proc. Nat. Acad. Sci. 97: 787-792, 2000. [PubMed: 10639158] [Full Text: https://doi.org/10.1073/pnas.97.2.787]
Schonk, D., van Dijk, P., Riegmann, P., Trapman, J., Holm, C., Willcocks, T. C., Sillekens, P., van Venrooij, W., Wimmer, E., Geurts van Kessel, A., Ropers, H.-H., Wieringa, B. Assignment of seven genes to distinct intervals on the midportion of human chromosome 19q surrounding the myotonic dystrophy gene region. Cytogenet. Cell Genet. 54: 15-19, 1990. [PubMed: 1701111] [Full Text: https://doi.org/10.1159/000132946]
Udpa, N., Ronen, R., Zhou, D., Liang, J., Stobdan, T., Appenzeller, O., Yin, Y., Du, Y., Guo, L., Cao, R., Wang, Y., Jin, X., and 15 others. Whole genome sequencing of Ethiopian highlanders reveals conserved hypoxia tolerance genes. Genome Biol. 15: R36, 2014. Note: Electronic Article. [PubMed: 24555826] [Full Text: https://doi.org/10.1186/gb-2014-15-2-r36]
Wang, S., Lapierre, P., Robert, M.-F., Nadeau, J. H., Mitchell, G. A. Hormone-sensitive lipase maps to proximal chromosome 7 in mice and is genetically distinct from the Ad and Tub loci. Genomics 24: 416-417, 1994. [PubMed: 7698777] [Full Text: https://doi.org/10.1006/geno.1994.1646]
Zolotov, S., Xing, C., Mahamid, R., Shalata, A., Sheikh-Ahmad, M., Garg, A. Homozygous LIPE mutation in siblings with multiple symmetric lipomatosis, partial lipodystrophy, and myopathy. Am. J. Med. Genet. 173A: 190-194, 2017. [PubMed: 27862896] [Full Text: https://doi.org/10.1002/ajmg.a.37880]