Long-Term Dietary Taurine Lowers Plasma Levels of Cholesterol and Bile Acids

Abstract

Cholesterol is an essential lipid in vertebrates, but excess blood cholesterol promotes atherosclerosis. In the liver, cholesterol is metabolized to bile acids by cytochrome P450, family 7, subfamily a, polypeptide 1 (CYP7A1), the transcription of which is negatively regulated by the ERK pathway. Fibroblast growth factor 21 (FGF21), a hepatokine, induces ERK phosphorylation and suppresses Cyp7a1 transcription. Taurine, a sulfur-containing amino acid, reportedly promotes cholesterol metabolism and lowers blood and hepatic cholesterol levels. However, the influence of long-term feeding of taurine on cholesterol levels and metabolism remains unclear. Here, to evaluate the more chronic effects of taurine on cholesterol levels, we analyzed mice fed a taurine-rich diet for 14-16 weeks. Long-term feeding of taurine lowered plasma cholesterol and bile acids without significantly changing other metabolic parameters, but hardly affected these levels in the liver. Moreover, taurine upregulated Cyp7a1 levels, while downregulated phosphorylated ERK and Fgf21 levels in the liver. Likewise, taurine-treated Hepa1-6 cells, a mouse hepatocyte line, exhibited downregulated Fgf21 levels and upregulated promoter activity of Cyp7a1. These results indicate that taurine promotes cholesterol metabolism by suppressing the FGF21/ERK pathway followed by upregulating Cyp7a1 expression. Collectively, this study shows that long-term feeding of taurine lowers both plasma cholesterol and bile acids, reinforcing that taurine effectively prevents hypercholesterolemia.

Keywords: CYP7A1; ERK; FGF21; bile acid; cholesterol; taurine.

Figure 1

Taurine lowered plasma cholesterol and bile acids: Plasma total cholesterol (t-cholesterol) (n = 5) (A), bile acids (n = 4) (B), triglyceride (TG) (n = 5) (C), non-esterified fatty acids (NEFA) (n = 5) (D), t-cholesterol (n = 10–11) (E), and bile acids (n = 5) (F) in the liver, and bile acids (G) in feces (n = 4) of Chow and TauD groups. Values represent means ± SD. Differences between values were statistically evaluated by Student’s t-test. * p < 0.05, ** p < 0.01 vs. Chow.

Figure 2

Taurine downregulated FGF21/ERK pathway and upregulated Cyp7a1 transcription in the liver: (A) The expression of Cyp7a1 mRNA in the liver was analyzed by real-time RT-PCR (n = 6). (B) Total protein extracted from the liver was analyzed by immunoblotting using the shown antibodies (n = 6). The left panels show representative images. The right graphs show quantitative data. GAPDH was used as a loading control. (C) The expression of Fgf21 mRNA in the liver was analyzed by real-time RT-PCR (n = 6). (D) Plasma FGF21 was quantified using ELISA (n = 6). Data of real-time RT-PCR were normalized to Tbp levels. Values represent means ± SD. Differences between values were statistically evaluated by Student’s t-test. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. Chow.

Figure 3

Taurine downregulated Fdf21 levels and induced Cyp7a1 promoter activity in Hepa1-6 cells: (A) Total protein extracted from Hepa1-6 cells treated with the indicated concentrations of taurine for 24 h was analyzed by immunoblotting using the shown antibodies (n = 4). The left panels show representative images. The right graphs show quantitative data. LaminB1 was used as a loading control. (B) The expression of Fgf21 mRNA in 10 mM taurine-treated Hepa1-6 cells (Tau) was analyzed by real-time RT-PCR. Data were normalized to Rps18 (n = 6). (C) Luciferase assay of Cyp7a1 in 10 mM taurine-treated Hepa1-6 cells (Tau). Relative luminescent units (RLU) were calculated as shown in the Materials and Methods section (n = 4). Values represent means ± SD. Differences between values were statistically evaluated by Dunnett’s test (A) or Student’s t-test (B,C). * p < 0.05 vs. Control.

Figure 4

A schematic diagram of the effects of long-term dietary taurine. Taurine upregulates the transcriptional activity of Cyp7a1 by suppressing FGF21 production in the liver. Bile acids are converted from blood cholesterol by CYP7A1 and more efficiently enter the enterohepatic circulation via taurine conjugation.