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Loss of small heterodimer partner expression in the liver protects against dyslipidemia

Helen B Hartman1, Kehdih Lai, Mark J Evans

  • 1Cardiovascular and Metabolic Disease Research, Wyeth Research, Collegeville, PA 19426, USA.

Journal of Lipid Research
|September 30, 2008
PubMed

Insights

Deleting small heterodimer partner (SHP) protects mice from high cholesterol and related liver issues. Inhibiting SHP may offer protection against dyslipidemia.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Genetics

Background:

  • Cholesterol 7alpha-hydroxylase (CYP7A1) converts cholesterol to bile acids, protecting against dyslipidemia and atherosclerosis.
  • FXR and SHP nuclear receptors repress CYP7A1 expression.

Purpose of the Study:

  • To investigate the role of SHP in regulating lipid metabolism and protecting against diet- and hypothyroidism-induced dyslipidemia.

Main Methods:

  • Utilized SHP-deficient (SHP(-/-)) mice on a 129 strain background and a mixed 129-C57Bl/6 background.
  • Employed LDLR(-/-) and LDLR(-/-)SHP(-/-) mice fed a Western diet.
  • Administered cholesterol/cholic acid (chol/CA) diet and induced hypothyroidism.
  • Performed hepatocyte-specific deletion of SHP.

Main Results:

  • SHP(-/-) mice were protected against hypercholesterolemia induced by chol/CA diet or hypothyroidism.
  • LDLR(-/-)SHP(-/-) mice showed reduced serum VLDL and LDL cholesterol and triglyceride levels compared to LDLR(-/-) mice on a Western diet.
  • Hepatic inflammation was abolished in LDLR(-/-)SHP(-/-) mice.
  • Western diet induced CYP7A1 expression 10-fold in LDLR(-/-)SHP(-/-) mice but not in LDLR(-/-) mice.
  • Hepatocyte-specific SHP deletion protected against dyslipidemia.

Conclusions:

  • Selective inhibition of hepatic SHP expression may protect against dyslipidemia.
  • SHP plays a critical role in regulating hepatic lipid metabolism and response to dyslipidemic conditions.

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