Intestine-specific DGAT1 deficiency improves atherosclerosis in apolipoprotein E knockout mice by reducing systemic cholesterol burden

Abstract

Background and aims 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 Dgat1 have reduced intestinal cholesterol absorption and potentiated macrophage cholesterol efflux, and consequently, exhibit attenuated atherogenesis. However, he-matopoietic 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. Methods We generated intestine-specific Dgat1 −/− mice on the ApoE −/− background ( iDgat1 −/− ApoE −/− ) and determined cholesterol homeostasis and atherosclerosis development. Results When 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. Conclusions Disruption 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.

Lycopene Reduces Cholesterol Absorption and Prevents Atherosclerosis in ApoE–/– Mice by Downregulating HNF-1α and NPC1L1 Expression

“…Immunohistochemical analysis was performed on small intestine tissues to observe the expression of NPC1L1 and HNF-1α as previously described. , In brief, the small intestine was fixed with 4% paraformaldehyde and then embedded in paraffin. Paraffin wax blocks were prepared and sliced.…”

“…The aortic atherosclerosis lesions were determined according to the method described previously . Briefly, the active vessel cavity was rinsed with normal saline until the rinse solution became clear.…”

Modeling the cell biology of monogenetic intestinal epithelial disorders

“…Furthermore, cell lines may provide an alternative for modeling when mouse models are not relevant to the human biology. Such is the case for DGAT1, where the homologous DGAT1 gene and its cousin DGAT2 are not expressed in rodents as in humans, and deletion of one or other of DGAT genes in mice does not phenocopy the syndrome in humans ( Chen and Farese, 2005 ; Gluchowski et al, 2017 ; Vujić et al, 2020 ). Nevertheless, DGAT1 knockdown could be performed in CaCo2-BBe cells with recapitulation of the impairment in brush border integrity and amelioration of the phenotype with culturing without lipids in the apical media ( Schlegel et al, 2018 ).…”

The year 2020 in Atherosclerosis

“…The molecular regulation of intestinal lipoprotein metabolism is still unclear, and van Loon et al [13] tested if the liver X receptor (LXR)-E3 ubiquitin ligase inducible degrader of LDLR (IDOL)-low-density lipoprotein receptor (LDLR) axis regulates intestinal expression of LDLR, and found that it is critical for maintaining cholesterol homeostasis in enterocytes. Vujić et al [14] demonstrated that suppressed intestinal expression of acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), the rate-limiting enzyme of triglyceride biosynthesis, reduces dietary cholesterol assimilation in the intestine, and consequently atherogenesis. This finding underlines the role of intestinal-derived lipoproteins in ASCVD.…”