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. 1998 Jan 1;101(1):145–152. doi: 10.1172/JCI791

Hyperlipidemia and cutaneous abnormalities in transgenic mice overexpressing human apolipoprotein C1.

M C Jong 1, M J Gijbels 1, V E Dahlmans 1, P J Gorp 1, S J Koopman 1, M Ponec 1, M H Hofker 1, L M Havekes 1
PMCID: PMC508550  PMID: 9421476

Abstract

Transgenic mice were generated with different levels of human apolipoprotein C1 (APOC1) expression in liver and skin. At 2 mo of age, serum levels of cholesterol, triglycerides (TG), and FFA were strongly elevated in APOC1 transgenic mice compared with wild-type mice. These elevated levels of serum cholesterol and TG were due mainly to an accumulation of VLDL particles in the circulation. In addition to hyperlipidemia, APOC1 transgenic mice developed dry and scaly skin with loss of hair, dependent on the amount of APOC1 expression in the skin. Since these skin abnormalities appeared in two independent founder lines, a mutation related to the specific insertion site of the human APOC1 gene as the cause for the phenotype can be excluded. Histopathological analysis of high expressor APOC1 transgenic mice revealed a disorder of the skin consisting of epidermal hyperplasia and hyperkeratosis, and atrophic sebaceous glands lacking sebum. In line with these results, epidermal lipid analysis showed that the relative amounts of the sebum components TG and wax diesters in the epidermis of high expressor APOC1 transgenic mice were reduced by 60 and 45%, respectively. In addition to atrophic sebaceous glands, the meibomian glands were also found to be severely atrophic in APOC1 transgenic mice. High expressor APOC1 transgenic mice also exhibited diminished abdominal adipose tissue stores (a 60% decrease compared with wild-type mice) and a complete deficiency of subcutaneous fat. These results indicate that, in addition to the previously reported inhibitory role of apoC1 on hepatic remnant uptake, overexpression of apoC1 affects lipid synthesis in the sebaceous gland and/or epidermis as well as adipose tissue formation. These APOC1 transgenic mice may serve as an interesting in vivo model for the investigation of lipid homeostasis in the skin.

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Selected References

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  1. BLIGH E. G., DYER W. J. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959 Aug;37(8):911–917. doi: 10.1139/o59-099. [DOI] [PubMed] [Google Scholar]
  2. Breslau-Siderius E. J., Toonstra J., Baart J. A., Koppeschaar H. P., Maassen J. A., Beemer F. A. Ectodermal dysplasia, lipoatrophy, diabetes mellitus, and amastia: a second case of the AREDYLD syndrome. Am J Med Genet. 1992 Oct 1;44(3):374–377. doi: 10.1002/ajmg.1320440321. [DOI] [PubMed] [Google Scholar]
  3. Brown W. R., Hardy M. H. A hypothesis on the cause of chronic epidermal hyperproliferation in asebia mice. Clin Exp Dermatol. 1988 Mar;13(2):74–77. doi: 10.1111/j.1365-2230.1988.tb00661.x. [DOI] [PubMed] [Google Scholar]
  4. Church G. M., Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. doi: 10.1073/pnas.81.7.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Downing D. T., Strauss J. S., Pochi P. E. Changes in skin surface lipid composition induced by severe caloric restriction in man. Am J Clin Nutr. 1972 Apr;25(4):365–367. doi: 10.1093/ajcn/25.4.365. [DOI] [PubMed] [Google Scholar]
  6. Fort P., Marty L., Piechaczyk M., el Sabrouty S., Dani C., Jeanteur P., Blanchard J. M. Various rat adult tissues express only one major mRNA species from the glyceraldehyde-3-phosphate-dehydrogenase multigenic family. Nucleic Acids Res. 1985 Mar 11;13(5):1431–1442. doi: 10.1093/nar/13.5.1431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Frykman P. K., Brown M. S., Yamamoto T., Goldstein J. L., Herz J. Normal plasma lipoproteins and fertility in gene-targeted mice homozygous for a disruption in the gene encoding very low density lipoprotein receptor. Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8453–8457. doi: 10.1073/pnas.92.18.8453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gates A. H., Arundell F. D., Karasek M. A. Hereditary defect of the pilosebaceous unit in a new double mutant mouse. J Invest Dermatol. 1969 Feb;52(2):115–118. doi: 10.1038/jid.1969.18. [DOI] [PubMed] [Google Scholar]
  9. Gates A. H., Karasek M. Hereditary Absence of Sebaceous Glands in the Mouse. Science. 1965 Jun 11;148(3676):1471–1473. doi: 10.1126/science.148.3676.1471. [DOI] [PubMed] [Google Scholar]
  10. Jong M. C., Dahlmans V. E., van Gorp P. J., Breuer M. L., Mol M. J., van der Zee A., Frants R. R., Hofker M. H., Havekes L. M. Both lipolysis and hepatic uptake of VLDL are impaired in transgenic mice coexpressing human apolipoprotein E*3Leiden and human apolipoprotein C1. Arterioscler Thromb Vasc Biol. 1996 Aug;16(8):934–940. doi: 10.1161/01.atv.16.8.934. [DOI] [PubMed] [Google Scholar]
  11. Jong M. C., Dahlmans V. E., van Gorp P. J., van Dijk K. W., Breuer M. L., Hofker M. H., Havekes L. M. In the absence of the low density lipoprotein receptor, human apolipoprotein C1 overexpression in transgenic mice inhibits the hepatic uptake of very low density lipoproteins via a receptor-associated protein-sensitive pathway. J Clin Invest. 1996 Nov 15;98(10):2259–2267. doi: 10.1172/JCI119036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jong M. C., van Ree J. H., Dahlmans V. E., Frants R. R., Hofker M. H., Havekes L. M. Reduced very-low-density lipoprotein fractional catabolic rate in apolipoprotein C1-deficient mice. Biochem J. 1997 Jan 15;321(Pt 2):445–450. doi: 10.1042/bj3210445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Lauer S. J., Walker D., Elshourbagy N. A., Reardon C. A., Levy-Wilson B., Taylor J. M. Two copies of the human apolipoprotein C-I gene are linked closely to the apolipoprotein E gene. J Biol Chem. 1988 May 25;263(15):7277–7286. [PubMed] [Google Scholar]
  14. Nicolaides N., Santos E. C. The di- and triesters of the lipids of steer and human meibomian glands. Lipids. 1985 Jul;20(7):454–467. doi: 10.1007/BF02534237. [DOI] [PubMed] [Google Scholar]
  15. Pinheiro M., Freire-Maia N., Chautard-Freire-Maia E. A., Araujo L. M., Liberman B. AREDYLD: a syndrome combining an acrorenal field defect, ectodermal dysplasia, lipoatrophic diabetes, and other manifestations. Am J Med Genet. 1983 Sep;16(1):29–33. doi: 10.1002/ajmg.1320160106. [DOI] [PubMed] [Google Scholar]
  16. Pochi P. E., Downing D. T., Strauss J. S. Sebaceous gland response in man to prolonged total caloric deprivation. J Invest Dermatol. 1970 Nov;55(5):303–309. doi: 10.1111/1523-1747.ep12260136. [DOI] [PubMed] [Google Scholar]
  17. Ponec M., Weerheim A., Kempenaar J., Mommaas A. M., Nugteren D. H. Lipid composition of cultured human keratinocytes in relation to their differentiation. J Lipid Res. 1988 Jul;29(7):949–961. [PubMed] [Google Scholar]
  18. RANDLE P. J., GARLAND P. B., HALES C. N., NEWSHOLME E. A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963 Apr 13;1(7285):785–789. doi: 10.1016/s0140-6736(63)91500-9. [DOI] [PubMed] [Google Scholar]
  19. Shachter N. S., Ebara T., Ramakrishnan R., Steiner G., Breslow J. L., Ginsberg H. N., Smith J. D. Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein Cl. J Clin Invest. 1996 Aug 1;98(3):846–855. doi: 10.1172/JCI118857. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Shachter N. S., Zhu Y., Walsh A., Breslow J. L., Smith J. D. Localization of a liver-specific enhancer in the apolipoprotein E/C-I/C-II gene locus. J Lipid Res. 1993 Oct;34(10):1699–1707. [PubMed] [Google Scholar]
  21. Simonet W. S., Bucay N., Lauer S. J., Taylor J. M. A far-downstream hepatocyte-specific control region directs expression of the linked human apolipoprotein E and C-I genes in transgenic mice. J Biol Chem. 1993 Apr 15;268(11):8221–8229. [PubMed] [Google Scholar]
  22. Simonet W. S., Bucay N., Pitas R. E., Lauer S. J., Taylor J. M. Multiple tissue-specific elements control the apolipoprotein E/C-I gene locus in transgenic mice. J Biol Chem. 1991 May 15;266(14):8651–8654. [PubMed] [Google Scholar]
  23. Smit M., van der Kooij-Meijs E., Frants R. R., Havekes L., Klasen E. C. Apolipoprotein gene cluster on chromosome 19. Definite localization of the APOC2 gene and the polymorphic Hpa I site associated with type III hyperlipoproteinemia. Hum Genet. 1988 Jan;78(1):90–93. doi: 10.1007/BF00291243. [DOI] [PubMed] [Google Scholar]
  24. Soutar A. K., Garner C. W., Baker H. N., Sparrow J. T., Jackson R. L., Gotto A. M., Smith L. C. Effect of the human plasma apolipoproteins and phosphatidylcholine acyl donor on the activity of lecithin: cholesterol acyltransferase. Biochemistry. 1975 Jul 15;14(14):3057–3064. doi: 10.1021/bi00685a003. [DOI] [PubMed] [Google Scholar]
  25. Stewart M. E., Downing D. T. Chemistry and function of mammalian sebaceous lipids. Adv Lipid Res. 1991;24:263–301. doi: 10.1016/b978-0-12-024924-4.50013-4. [DOI] [PubMed] [Google Scholar]
  26. Tiffany J. M. The lipid secretion of the meibomian glands. Adv Lipid Res. 1987;22:1–62. doi: 10.1016/b978-0-12-024922-0.50005-9. [DOI] [PubMed] [Google Scholar]
  27. Weinstock P. H., Bisgaier C. L., Aalto-Setälä K., Radner H., Ramakrishnan R., Levak-Frank S., Essenburg A. D., Zechner R., Breslow J. L. Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes. J Clin Invest. 1995 Dec;96(6):2555–2568. doi: 10.1172/JCI118319. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Wilkinson D. I., Karasek M. A. Skin lipids of a normal and mutant (asebic) mouse strain. J Invest Dermatol. 1966 Nov;47(5):449–455. doi: 10.1038/jid.1966.168. [DOI] [PubMed] [Google Scholar]
  29. Wilkinson D. I., Karasek M. A. Skin lipids of a normal and mutant (asebic) mouse strain. J Invest Dermatol. 1966 Nov;47(5):449–455. doi: 10.1038/jid.1966.168. [DOI] [PubMed] [Google Scholar]
  30. Yamamoto T., Hoshino A., Takahashi S., Kawarabayasi Y., Iijima H., Sakai J. The role of the very low density lipoprotein receptor in the metabolism of plasma lipoproteins containing ApoE. Ann N Y Acad Sci. 1995 Jan 17;748:217–225. doi: 10.1111/j.1749-6632.1994.tb17321.x. [DOI] [PubMed] [Google Scholar]
  31. Zannis V. I., McPherson J., Goldberger G., Karathanasis S. K., Breslow J. L. Synthesis, intracellular processing, and signal peptide of human apolipoprotein E. J Biol Chem. 1984 May 10;259(9):5495–5499. [PubMed] [Google Scholar]
  32. van Ree J. H., Hofker M. H., van den Broek W. J., van Deursen J. M., van der Boom H., Frants R. R., Wieringa B., Havekes L. M. Increased response to cholesterol feeding in apolipoprotein C1-deficient mice. Biochem J. 1995 Feb 1;305(Pt 3):905–911. doi: 10.1042/bj3050905. [DOI] [PMC free article] [PubMed] [Google Scholar]

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