Domains of apolipoprotein E contributing to triglyceride and cholesterol homeostasis in vivo. Carboxyl-terminal region 203-299 promotes hepatic very low density lipoprotein-triglyceride secretion

J Biol Chem. 2001 Jun 8;276(23):19778-86. doi: 10.1074/jbc.M100418200. Epub 2001 Feb 9.

Abstract

Apolipoprotein (apo) E has been implicated in cholesterol and triglyceride homeostasis in humans. At physiological concentration apoE promotes efficient clearance of apoE-containing lipoprotein remnants. However, high apoE plasma levels correlate with high plasma triglyceride levels. We have used adenovirus-mediated gene transfer in apoE-deficient mice (E(-)/-) to define the domains of apoE required for cholesterol and triglyceride homeostasis in vivo. A dose of 2 x 10(9) plaque-forming units of apoE4-expressing adenovirus reduced slightly the cholesterol levels of E(-)/- mice and resulted in severe hypertriglyceridemia, due to accumulation of cholesterol and triglyceride-rich very low density lipoprotein particles in plasma. In contrast, the truncated form apoE4-202 resulted in a 90% reduction in the plasma cholesterol levels but did not alter plasma triglyceride levels in the E(-)/- mice. ApoE secretion by cell cultures, as well as the steady-state hepatic mRNA levels in individual mice expressing apoE4 or apoE4-202, were similar. In contrast, very low density lipoprotein-triglyceride secretion in mice expressing apoE4, but not apoE4-202, was increased 10-fold, as compared with mice infected with a control adenovirus. The findings suggest that the amino-terminal 1-202 region of apoE4 contains the domains required for the in vivo clearance of lipoprotein remnants. Furthermore, the carboxyl-terminal 203-299 residues of apoE promote hepatic very low density lipoprotein-triglyceride secretion and contribute to apoE-induced hypertriglyceridemia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Apolipoprotein E4
  • Apolipoproteins E / blood
  • Apolipoproteins E / chemistry
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism*
  • Base Sequence
  • Cholesterol / blood
  • Cholesterol / metabolism*
  • Chromatography, Liquid
  • DNA Primers
  • Female
  • Homeostasis*
  • Humans
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Triglycerides / blood
  • Triglycerides / metabolism*
  • Tumor Cells, Cultured

Substances

  • Apolipoprotein E4
  • Apolipoproteins E
  • DNA Primers
  • RNA, Messenger
  • Triglycerides
  • Cholesterol