Abstract
Background and aimsAcyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is the rate-limiting enzyme catalyzing the final step of triglyceride synthesis by esterifying a diglyceride with a fatty acid. We have previously shown that apolipoprotein E-knockout (ApoE−/−) mice lacking Dgat1 have reduced intestinal cholesterol absorption and potentiated macrophage cholesterol efflux, and consequently, exhibit attenuated atherogenesis. However, hematopoietic Dgat1 deficiency lacked beneficial effects on atherosclerosis. Due to our recent results on the critical role of intestinal Dgat1 in murine cholesterol homeostasis, we delineated whether intestinal Dgat1 deficiency regulates atherogenesis in mice. MethodsWe generated intestine-specific Dgat1−/− mice on the ApoE−/− background (iDgat1−/−ApoE−/−) and determined cholesterol homeostasis and atherosclerosis development. ResultsWhen fed a Western-type diet, iDgat1−/−ApoE−/− mice exhibited a substantial decrease in fasting plasma cholesterol content in ApoB-containing lipoproteins. Although lipid absorption was delayed, iDgat1−/−ApoE−/− mice had reduced acute and fractional cholesterol absorption coupled with an elevated fecal caloric loss. In line, increased appearance of i.v. administered [³H]cholesterol in duodena and stool of iDgat1−/−ApoE−/− animals suggested potentiated cholesterol elimination. Atherosclerotic lesions were markedly smaller with beneficial alterations in plaque composition as evidenced by reduced macrophage infiltration and necrotic core size despite unaltered collagen content, indicating improved plaque stability. ConclusionsDisruption of Dgat1 activity solely in the small intestine of ApoE−/− mice strongly decreased plasma cholesterol levels by abrogating the assimilation of dietary cholesterol, partly by reduced absorption and increased excretion. Consequently, the reduced cholesterol burden significantly attenuated atherogenesis and improved the lesion phenotype in iDgat1−/−ApoE−/− mice.
Highlights
The final and only committed step in triglyceride (TG) synthesis is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes
Fasting plasma lipid concentrations were comparable between chow diet-fed mice, Western-type diet (WTD)-fed iDgat1− /− apolipoprotein E (ApoE)− /− mice had >43% decreased total cholesterol (TC), free cholesterol (FC), and cholesteryl ester (CE) concentrations compared to controls (Table 1)
The reduction in circulating cholesterol concentrations was attributable to a profound decrease of cholesterol in ApoB-containing lipoproteins (very low-density lipoprotein (VLDL), LDL) (Fig. 1D) and associated with reduced plasma ApoB abundance (Supplementary Fig. 2), whereas high-density lipoprotein cholesterol was slightly increased in iDgat1− /− ApoE− /− mice (Fig. 1D)
Summary
The final and only committed step in triglyceride (TG) synthesis is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. N. Vujic et al. Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) is the rate-limiting enzyme catalyzing the final step of triglyceride synthesis by esterifying a diglyceride with a fatty acid. We have previously shown that apolipoprotein E-knockout (ApoE− /− ) mice lacking Dgat have reduced intestinal cholesterol absorption and potentiated macrophage cholesterol efflux, and exhibit attenuated atherogenesis. The reduced cholesterol burden significantly attenuated atherogenesis and improved the lesion phenotype in iDgat1− /− ApoE− /− mice
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have