Foxa2 activity increases plasma high density lipoprotein levels by regulating apolipoprotein M.
Obesity, diabetes, insulin resistance, and hyperinsulinemia are frequently associated with a cluster of closely related lipid abnormalities such as low plasma levels of high density lipoprotein (HDL) and elevated levels of triglyceride, both known to increase the risk of developing atherosclerotic disease. The molecular mechanisms linking obesity, insulin resistance, and hyperinsulinemia to low HDL levels are incompletely understood. Here we demonstrate that insulin, through a Foxa2-mediated mechanism, inhibited the expression of apolipoprotein M (apoM), an important determinant of plasma pre-beta-HDL and alpha-HDL concentrations. Obese mice had decreased apoM expression and plasma pre-beta-HDL levels due to inactivation of Foxa2 in hyperinsulinemic states. Nuclear reexpression of Foxa2 with a phosphorylation-deficient mutant Foxa2T156A (Ad-T156A) activated apoM expression and increased plasma pre-beta-HDL and alpha-HDL levels. In contrast, haploinsufficient Foxa2(+/-) mice exhibited decreased hepatic apoM expression and plasma pre-beta-HDL and HDL levels. The increase in plasma HDL levels and pre-beta-HDL formation by Foxa2 was mediated exclusively by apoM, as constitutive active expression of Foxa2 in apoM(-/-) mice had no effect on plasma HDL levels. Our results identify a fundamental mechanism by which insulin regulates plasma HDL levels in physiological and insulin-resistant states and thus have important implications for novel therapeutic approaches to prevent atherosclerosis.
Wolfrum
Christian
C
Institute of Molecular Systems Biology, Swiss Federal Institute of Technology, Eidgenössische Technische Hochschule Zürich, 8093 Zürich, Switzerland.
Howell
Jessica J
JJ
Ndungo
Esther
E
Stoffel
Markus
M
D000818:Animals; D001053:Apolipoproteins / Q000378:metabolism*; D000075243:Apolipoproteins M; D050197:Atherosclerosis / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005786:Gene Expression Regulation; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D054834:Lipocalins; D008075:Lipoproteins, HDL / Q000097:blood*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
C400523:APOM protein, human; C501623:ApoM protein, mouse; D001053:Apolipoproteins; D000075243:Apolipoproteins M; C496502:FOXA2 protein, human; D007328:Insulin; D054834:Lipocalins; D008075:Lipoproteins, HDL; D051542:Hepatocyte Nuclear Factor 3-beta