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. 2017 Dec 27;2(1):99-112.
doi: 10.1002/hep4.1129. eCollection 2018 Jan.

Deficiency of cholesterol 7α-hydroxylase in bile acid synthesis exacerbates alcohol-induced liver injury in mice

Ajay C Donepudi  1 , Jessica M Ferrell  1 , Shannon Boehme  1 , Hueng-Sik Choi  2 , John Y L Chiang  1
Affiliations

Deficiency of cholesterol 7α-hydroxylase in bile acid synthesis exacerbates alcohol-induced liver injury in mice

Ajay C Donepudi et al. Hepatol Commun. .

VSports - Abstract

Alcoholic fatty liver disease (AFLD) is a major risk factor for cirrhosis-associated liver diseases. Studies demonstrate that alcohol increases serum bile acids in humans and rodents. AFLD has been linked to cholestasis, although the physiologic relevance of increased bile acids in AFLD and the underlying mechanism of increasing the bile acid pool by alcohol feeding are still unclear. In this study, we used mouse models either deficient of or overexpressing cholesterol 7α-hydroxylase (Cyp7a1), the rate-limiting and key regulatory enzyme in bile acid synthesis, to study the effect of alcohol drinking in liver metabolism and inflammation VSports手机版. Mice were challenged with chronic ethanol feeding (10 days) plus a binge dose of alcohol by oral gavage (5 g/kg body weight). Alcohol feeding reduced bile acid synthesis gene expression but increased the bile acid pool size, hepatic triglycerides and cholesterol, and inflammation and injury in wild-type mice and aggravated liver inflammation and injury in Cyp7a1-deficient mice. Interestingly, alcohol-induced hepatic inflammation and injury were ameliorated in Cyp7a1 transgenic mice. Conclusion: Alcohol feeding alters hepatic bile acid and cholesterol metabolism to cause liver inflammation and injury, while maintenance of bile acid and cholesterol homeostasis protect against alcohol-induced hepatic inflammation and injury. Our findings indicate that CYP7A1 plays a key role in protection against alcohol-induced steatohepatitis. (Hepatology Communications 2018;2:99-112). .

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Figures

Figure 1
Figure 1
Cyp7a1 deficiency aggravated alcohol‐induced hepatic injury and increased cholesterol levels. (A) Left panel, hepatic Cyp7a1 mRNA expression in alcohol‐fed (n = 6) and pair‐fed control (n = 5) female and male WT and Cyp7a1 –/– mice. Right panel, blood alcohol levels in female WT and Cyp7a1 –/– mice. In experiments B to F, female WT and Cyp7a1 –/– mice were used for alcohol feeding (n = 6) and pair‐fed controls (n = 5). (B) Liver‐to‐body weight and adipose tissue‐to‐body weight ratio of alcohol‐fed and pair‐fed control WT and Cyp7a1 –/– female mice. (C) Serum ALT levels. (D) Serum cholesterol, triglyceride, and free fatty acid levels. (E) Hepatic triglyceride and cholesterol levels. (F) Hematoxylin and eosin staining of liver (left) and filipin (right) staining of hepatic free cholesterol in liver (magnification × 200). Results are mean ± SEM; * indicates significant difference between the groups indicated (P < 0.05). Abbreviations: B.W, body weight; chol, cholesterol; Con, control; EtOH, ethanol; FFA, free fatty acid; H&E, hematoxylin and eosin; LW, liver weight; TG, triglyceride; WT, wild‐type.
Figure 2
Figure 2
Alcohol feeding increased bile acid pool size and decreased bile acid synthesis gene expression in mice. WT and Cyp7a1 –/– female mice were used for alcohol feeding (n = 6) and pair‐fed controls (n = 5). (A) Hepatic mRNA expression of bile acid synthesis genes. (B) Hepatic Cyp7a1 protein expression (n = 3, each lane represents one mouse). (C) Hepatic bile acid synthesis protein expression (n = 3, each lane represents one mouse). (D) Bile acid pool and content in gallbladder, small intestine, liver, and serum. (E) Hepatic mRNA expression of alcohol metabolism genes. (F) Hepatic Cyp2e1 protein expression. Results are mean ± SEM; * indicates significant difference between the groups indicated (P < 0.05). Abbreviations: AU, arbitrary unit; Con, control; EtOH, ethanol; GAPDH, glyceraldehyde 3‐phosphate dehydrogenase; GB, gallbladder; WT, wild‐type.
Figure 3
Figure 3
Chronic plus binge alcohol feeding altered cholesterol and lipid metabolism. WT and Cyp7a1 –/– female mice were used for alcohol feeding (n = 6) and pair‐fed controls (n = 5). (A) Hepatic mRNA expression of bile acid transporters and regulators of bile acid synthesis. (B) Hepatic mRNA expression of lipoprotein genes. (C) Hepatic mRNA expression of fatty acid metabolism genes. (D) Hepatic nuclear Srebp1c protein expression. (E) Hepatic mRNA expression of cholesterol metabolism genes. Results are mean ± SEM; * indicates significant difference between the groups indicated (P < 0.05). Abbreviations: AU, arbitrary unit; Con, control; EtOH, ethanol; WT, wild‐type.
Figure 4
Figure 4
Lack of Cyp7a1 aggravated alcohol‐induced hepatic inflammation. WT and Cyp7a1 –/– female mice were used for alcohol feeding (n = 6) and pair‐fed controls (n = 5). (A) Hepatic mRNA expression of proinflammatory genes. (B) Hepatic mRNA expression of the inflammasome genes Nlrp3 and Casp1. (C) Hepatic protein levels of pro‐Casp1 and Casp1 (p20) isoforms (n = 3, each lane represents one mouse). (D) Hepatic mRNA expression of genes involved in neutrophil infiltration. (E) Ileum mRNA expression of bile acid transporter and FXR target genes. (F) Ileum mRNA expression of genes involved in cell adhesion and inflammation. Results are mean ± SEM; * indicates significant difference between the groups indicated (P < 0.05). Abbreviations: AU, arbitrary unit; Con, control; EtOH, ethanol; GAPDH, glyceraldehyde 3‐phosphate dehydrogenase; WT, wild‐type.
Figure 5
Figure 5
Alcohol reduces bile acid synthesis gene and protein expression along with liver bile acid content in mice overexpressing Cyp7a1. WT and Cyp7a1‐Tg male mice were used for alcohol feeding (n = 6) and pair‐fed controls (n = 5). (A) Serum ALT levels. (B) Hepatic triglyceride and cholesterol levels. (C) Hepatic mRNA expression of bile acid synthesis genes. (D) Hepatic Cyp7a1 protein expression (n = 3, each lane represents one mouse). (E) Hepatic bile acid synthesis protein expression (n = 3, each lane represents one mouse). (F) Bile acid pool and content in gallbladder, small intestine, liver, and serum. Results are mean ± SEM; * indicates significant difference between the groups indicated (P < 0.05). Abbreviations: AU, arbitrary unit; chol, cholesterol; Con, control; EtOH, ethanol; GAPDH, glyceraldehyde 3‐phosphate dehydrogenase; GB, gallbladder; TG, triglyceride; WT, wild‐type.
Figure 6
Figure 6
Overexpression of Cyp7a1 ameliorated alcohol‐induced liver injury. (A) Hepatic mRNA expression of alcohol metabolism genes. (B) Hepatic Cyp2e1 protein expression. (C) Hepatic mRNA expression of Fxr and FXR target genes. (D) Hepatic mRNA expression of inflammation genes. (E) Hepatic mRNA expression of the inflammasome genes Nlrp3 and Casp1. Results are mean ± SEM; * indicates significant difference between the groups indicated (P < 0.05). Abbreviations: AU, arbitrary unit; Con, control; EtOH, ethanol; GAPDH, glyceraldehyde 3‐phosphate dehydrogenase; WT, wild‐type.
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