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Primates highly responsive to dietary cholesterol up-regulate hepatic ACAT2, and less responsive primates do not.
Lawrence L Rudel1, Matthew Davis, Janet Sawyer
1Arteriosclerosis Research Program, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. lrudel@wfubmc.edu
The Journal of Biological Chemistry
|June 25, 2002
Summary
Dietary cholesterol increases liver acyl-CoA:cholesterol acyltransferase 2 (ACAT2) protein levels in responsive monkeys, suggesting a mechanism for regulating hypercholesterolemia. ACAT2, not gene transcription, appears key.
Area of Science:
- Biochemistry
- Metabolic Diseases
- Primate Physiology
Background:
- Liver acyl-CoA:cholesterol acyltransferase 2 (ACAT2) is the primary ACAT enzyme in primate hepatocytes.
- Dietary cholesterol significantly impacts cholesterol metabolism and can induce hypercholesterolemia.
- Primate species exhibit varying responsiveness to dietary cholesterol challenges.
Purpose of the Study:
- To investigate the role of liver ACAT2 in regulating diet-induced hypercholesterolemia in primates.
- To compare the responses of ACAT2 and ACAT1 to dietary cholesterol.
- To elucidate the mechanism by which dietary cholesterol affects hepatic ACAT2 levels.
Main Methods:
- Comparative study of cynomolgus (high response) and African green monkeys (low response) fed low and high cholesterol diets.
- Analysis of liver biopsies for cholesterol and cholesteryl ester concentrations.
- Measurement of hepatic cholesteryl oleate secretion rate via liver perfusion.
- Assay of liver microsomal ACAT activity and ACAT1/ACAT2 protein mass.
- Comparison of ACAT2 protein and mRNA levels in response to diet.
Main Results:
- Cynomolgus monkeys showed higher liver cholesterol and cholesteryl ester levels, and higher hepatic ACAT activity, despite lower dietary cholesterol intake.
- Dietary cholesterol significantly increased ACAT2 protein mass (3-fold) in cynomolgus monkeys, correlating with elevated free cholesterol.
- ACAT2 protein mass was strongly correlated with microsomal ACAT activity in both species.
- ACAT2 was not responsive to dietary cholesterol in African green monkeys at the mRNA or protein level.
- ACAT1 protein mass showed weaker correlation with ACAT activity.
Conclusions:
- Dietary cholesterol elevates hepatic free cholesterol in responsive primates (cynomolgus monkeys).
- This elevation in free cholesterol leads to increased ACAT2 protein levels in hepatocytes, likely through enhanced production or stabilization, not transcriptional regulation.
- ACAT2 plays a critical role in regulating hypercholesterolemia induced by dietary cholesterol in responsive primates.