Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice

Abstract

The importance of cholesterol ester synthesis by acyl CoA:cholesterol acyltransferase (ACAT) enzymes in intestinal and hepatic cholesterol metabolism has been unclear. We now demonstrate that ACAT2 is the major ACAT in mouse small intestine and liver, and suggest that ACAT2 deficiency has profound effects on cholesterol metabolism in mice fed a cholesterol-rich diet, including complete resistance to diet-induced hypercholesterolemia and cholesterol gallstone formation. The underlying mechanism involves the lack of cholesterol ester synthesis in the intestine and a resultant reduced capacity to absorb cholesterol. Our results indicate that ACAT2 has an important role in the response to dietary cholesterol, and suggest that ACAT2 inhibition may be a useful strategy for treating hypercholesterolemia or cholesterol gallstones.

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Figure 1: Generation of ACAT2-deficient mice.
Figure 2: Protection from diet-induced hypercholesterolemia in ACAT2-deficient mice.
Figure 3: Electron micrographs of negatively stained plasma lipoproteins (density < 1.063 gm/ml) from wild-type (left) and ACAT2-deficient female mice (right) fed the HF/HC diet.
Figure 4: Resistance to diet-induced cholesterol gallstone formation in ACAT2-deficient mice.
Figure 5: Cholesterol absorption in wild-type (▪) and ACAT2-deficient mice (□).
Figure 6: Absence of cholesterol accumulation in livers of ACAT2-deficient mice.

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Acknowledgements

We thank E. Moore and B. Jefferson for technical assistance; T. Yu for blastocyst injections; B. Tow for assistance with ACAT assays; D. Newland and D. Sanan for assistance with histology; J. Carroll, J. Hull and S. Gonzales for graphics; S. Ordway and G. Howard for editorial assistance; B. Taylor for manuscript preparation; and D. Mangelsdorf and H. Chen for comments on the manuscript. This work was supported by the National Institutes of Health grants HL57170 (to R.V.F.), HL60844 (to R.L.H.), HL09610 (to John Dietschy), NIH postdoctoral fellowship training grants (to K.K.B. and M.A.), a postdoctoral fellowship from the Austrian Science Fund (to S.N.) and the J. David Gladstone Institutes.

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Correspondence to Robert V. Farese Jr..

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Buhman, K., Accad, M., Novak, S. et al. Resistance to diet-induced hypercholesterolemia and gallstone formation in ACAT2-deficient mice. Nat Med 6, 1341–1347 (2000). https://doi.org/10.1038/82153

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