Mouse hepatic lipase alleles with variable effects on lipoprotein composition and size

Serena M. Pratt, Sally Chiu, Glenda M. Espinal, Noreene M. Shibata, Howard Wong, Craig H Warden

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

The structural features responsible for the activities of hepatic lipase (HL) can be clarified by in vivo comparisons of naturally occurring variants. The coding sequence of HL from C57BL/6J (B6) and SPRET/EiJ (SPRET) mice differs by four amino acids (S106N, A156V, L416V, S480T); however, these changes are not predicted to influence HL function. To test for allelic effects, we generated SPRET-HL transgenics with physiological levels of HL mRNA and HL activity that was parallel in female transgenics and about 70% higher in male transgenics, toward tri-[3H]oleate, compared with B6 controls. We found no correlation between activity levels and plasma lipids. However, significant allelic effects on plasma lipids were observed. Compared with B6-HL, SPRET-HL mediated reductions in total cholesterol (TC) and VLDL-, LDL- and HDL-cholesterol and HDL-triglyceride (TG) in fed males, and SPRET-HL decreased total TG and VLDL- and HDLTG levels in fasted males. Fasted female transgenics had reduced TC compared with controls. We also found allele and sex effects on lipoprotein particle size. Male transgenic mice had increased VLDL and decreased LDL size, and female transgenic mice had decreased HDL size compared with control animals. These findings demonstrate highly divergent effects of naturally occurring HL coding sequence variants on lipid and lipoprotein metabolism.

Original languageEnglish (US)
Pages (from-to)1035-1048
Number of pages14
JournalJournal of Lipid Research
Volume51
Issue number5
DOIs
StatePublished - May 1 2010

Keywords

  • 129 donor allele
  • Allele
  • Hepatic lipase
  • Lipoprotein
  • Natural variant
  • Obesity
  • SPRET/Ei
  • Transgenic

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

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