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. 2013 Sep;27(9):3805-17.
doi: 10.1096/fj.12-223008. Epub 2013 Jun 10.

Hyodeoxycholic acid improves HDL function and inhibits atherosclerotic lesion formation in LDLR-knockout mice

Diana M Shih  1 , Zory Shaposhnik, Yonghong Meng, Melenie Rosales, Xuping Wang, Judy Wu, Boris Ratiner, Filiberto Zadini, Giorgio Zadini, Aldons J Lusis
Affiliations

Hyodeoxycholic acid improves HDL function and inhibits atherosclerotic lesion formation in LDLR-knockout mice

Diana M Shih et al. FASEB J. 2013 Sep.

Abstract

We examined the effects of a natural secondary bile acid, hyodeoxycholic acid (HDCA), on lipid metabolism and atherosclerosis in LDL receptor-null (LDLRKO) mice. Female LDLRKO mice were maintained on a Western diet for 8 wk and then divided into 2 groups that received chow, or chow + 1.25% HDCA, diets for 15 wk. We observed that mice fed the HDCA diet were leaner and exhibited a 37% (P<0.05) decrease in fasting plasma glucose level. HDCA supplementation significantly decreased atherosclerotic lesion size at the aortic root region, the entire aorta, and the innominate artery by 44% (P<0.0001), 48% (P<0.01), and 94% (P<0.01), respectively, as compared with the chow group. Plasma VLDL/IDL/LDL cholesterol levels were significantly decreased, by 61% (P<0.05), in the HDCA group as compared with the chow diet group. HDCA supplementation decreased intestinal cholesterol absorption by 76% (P<0.0001) as compared with the chow group. Furthermore, HDL isolated from the HDCA group exhibited significantly increased ability to mediate cholesterol efflux ex vivo as compared with HDL of the chow diet group. In addition, HDCA significantly increased the expression of genes involved in cholesterol efflux, such as Abca1, Abcg1, and Apoe, in a macrophage cell line. Thus, HDCA is a candidate for antiatherosclerotic drug therapy.

Keywords: bile acid; high-density lipoprotein; intestinal cholesterol absorption; low-density lipoprotein; reverse cholesterol transport.

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Figures

Figure 1.
Figure 1.
Atherosclerotic lesion size and composition of LDLRKO mice fed with various diets. After 8 wk of Western diet feeding (baseline), mice were switched to chow diet or chow diet supplemented with HDCA for another 15 wk. A–C) Atherosclerotic lesion size measurements at the aortic root region (A), in the entire aorta (B), and in the innominate artery region (C). Lines and error bars indicate mean ± se lesion area of each group. D, E) Relative macrophage content (D) and smooth muscle cell content (E) in the atherosclerotic lesions of the aortic root region were determined by immunohistochemistry using antibodies against CD68 and α-actin, respectively; 4–6 mice/group with 3–5 lesion sections/mouse were used in the study. *P < 0.05, **P < 0.01, ***P < 0.0001; ###P < 0.0001 vs. baseline group.
Figure 2.
Figure 2.
Plasma lipoprotein analysis of LDLRKO mice that received various diets. Pooled plasma samples from 5 mice/diet group that received chow or chow + HDCA diets for 3 wk were used for FPLC analysis. A–C) FPLC fractions were used to quantify total cholesterol (A), phospholipid (B), and triglyceride (C) concentrations. See Table 6 for lipid composition of VLDL and IDL/LDL from diet groups. D) The apoB-48, apoB-100, and apoE contents of the VLDL fractions (lanes 12–15) and LDL fractions (lanes 24–27) collected from FPLC were examined by immunoblotting as described in Materials and Methods.
Figure 3.
Figure 3.
Intestinal cholesterol absorption, fecal lipid content, and gene expression in the small intestine of LDLRKO mice that received 3 wk feeding of chow diet or chow diet supplemented with HDCA. A) Intestinal cholesterol absorption rate. B) Daily fecal excretion of cholesterol, triglycerides, and bile acids. C) Small intestine expression of genes involved in cholesterol and bile acid transport of LDLRKO mice fed the chow or chow + HDCA diet. *P < 0.05, **P < 0.01, ***P < 0.0001 vs. chow diet group.
Figure 4.
Figure 4.
Liver lipid content, bile composition, and liver gene expression in the LDLRKO mice that received various diets for 3 wk. A) Liver lipid content was determined as described in Materials and Methods. B) Cholesterol, phophatdylcholine (PC), and total bile acids concentrations of bile collected from the gallbladder were examined. C) Hepatic expression of genes involved in cholesterol and bile acids homeostasis and gluconeogenesis was examined. *P < 0.05, **P < 0.01, ***P < 0.0001 vs. chow diet group.
Figure 5.
Figure 5.
Examination of HDL properties and cholesterol efflux ability of HDL isolated from LDLRKO mice that received various diets, and the effect of HDCA treatment on expression of genes involved in cholesterol efflux in RAW 264.7 cells. A–D) HDL samples were isolated from pooled plasma of mice fed the chow or chow + HDCA diets by FPLC and used in immunoblotting using an antibody against mouse apoA1 (A), determination of total bile acid levels in HDL and plasma (B), examination of extent of lipid oxidation by the DCF assay (C), and cholesterol efflux assay as described in Materials and Methods (D). *P < 0.05, **P < 0.01, ***P < 0.0001 vs. chow diet group. E) Gene expression analysis of RAW 264.7 cells treated with DMSO (vehicle) or 50 or 100 μM of HDCA for 24 h. *P < 0.05, **P < 0.01, ***P < 0.0001 vs. DMSO group.
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