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. 2010 Aug;52(2):678-90.
doi: 10.1002/hep.23721.

Transgenic expression of cholesterol 7alpha-hydroxylase in the liver prevents high-fat diet-induced obesity and insulin resistance in mice

Tiangang Li  1 , Erika Owsley, Michelle Matozel, Peter Hsu, Colleen M Novak, John Y L Chiang
Affiliations

VSports - Transgenic expression of cholesterol 7alpha-hydroxylase in the liver prevents high-fat diet-induced obesity and insulin resistance in mice

"VSports app下载" Tiangang Li et al. Hepatology. 2010 Aug.

Abstract

Cholesterol 7alpha-hydroxylase (CYP7A1) is the rate-limiting enzyme in the bile acid biosynthetic pathway that converts cholesterol into bile acids in the liver. Recent studies have shown that bile acids may play an important role in maintaining lipid, glucose, and energy homeostasis. However, the role of CYP7A1 in the development of obesity and diabetes is currently unclear. In this study, we demonstrated that transgenic mice overexpressing Cyp7a1 in the liver [i. e. , Cyp7a1 transgenic (Cyp7a1-tg) mice] were resistant to high-fat diet (HFD)-induced obesity, fatty liver, and insulin resistance VSports手机版. Cyp7a1-tg mice showed increased hepatic cholesterol catabolism and an increased bile acid pool. Cyp7a1-tg mice had increased secretion of hepatic very low density lipoprotein but maintained plasma triglyceride homeostasis. Gene expression analysis showed that the hepatic messenger RNA expression levels of several critical lipogenic and gluconeogenic genes were significantly decreased in HFD-fed Cyp7a1-tg mice. HFD-fed Cyp7a1-tg mice had increased whole body energy expenditure and induction of fatty acid oxidation genes in the brown adipose tissue. .

Conclusion: This study shows that Cyp7a1 plays a critical role in maintaining whole body lipid, glucose, and energy homeostasis V体育安卓版. The induction of CYP7A1 expression with the expansion of the hydrophobic bile acid pool may be a potential therapeutic strategy for treating metabolic disorders such as fatty liver diseases, obesity, and diabetes in humans. .

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"V体育官网入口" Conflict of interest statement

Potential conflict of interest: Nothing to report.

Figures

Fig. 1
Fig. 1
Tg expression of Cyp7a1 in the mouse liver prevented weight gain and reduced adiposity. Female WT or Cyp7a1-tg mice were fed either a chow diet or HFD for 4 months, and (A,B) the body weight, (C) body composition, (D) visceral fat mass, (E) H&E staining of adipocytes, and (F) food intake were determined. Results are expressed as means and standard errors (n =6–10). *Statistically significant difference (P < 0.05) versus WT mice on chow; **statistically significant difference (P < 0.05) versus WT mice on an HFD. Abbreviations: Tg, transgenic; WT, wild-type.
Fig. 2
Fig. 2
Tg expression of Cyp7a1 in the mouse liver prevented fatty liver. Female CYP7A1-tg mice were fed chow or an HFD for 4 months. Mice were fasted overnight. (A) The liver weight was determined. (B) H&E staining and Oil Red O staining of liver sections. Arrows indicate unstained lipid inclusions. (C,D) Hepatic cholesterol and TG contents. (E) Serum ALT levels in WT and CYP7A1-tg mice fed an HFD. Results are expressed as means and standard errors (n =8–10). *Statistically significant difference (P < 0.05) versus chow-fed WT mice; **statistically significant difference (P < 0.05) versus HFD-fed WT mice. Abbreviations: ALT, alanine aminotransferase; Tg, transgenic; WT, wild-type.
Fig. 3
Fig. 3
Cyp7a1-tg mice showed increased hepatic VLDL secretion but maintained plasma TG homeostasis. Female mice were fed an HFD for 4 months. (A) Mice were briefly fasted for 4 hours, and the hepatic VLDL secretion was assayed after an intraperitoneal injection of taloxapol. (B,C) Hepatic mRNA and protein expression of MTP in mice fed for 4 hours after overnight fasting. Liver samples were pooled from six mice per group for western blot analysis of MTP protein. (DF) Plasma cholesterol, TG, and FFA levels in mice fasted overnight. Results are expressed as means and standard errors (n =6–8). *Statistically significant difference (P < 0.05) versus chow-fed WT mice; **statistically significant difference (P < 0.05) versus HFD-fed WT mice. Abbreviations: Tg, transgenic; WT, wild-type.
Fig. 4
Fig. 4
FPLC analysis of the plasma lipoprotein profile for HFD-fed WT and Cyp7a1-tg male and female mice. Mice were fed an HFD for 4 month. After 6 hours of fasting, serum was collected and pooled (four mice per group). Serum lipoproteins were separated by FPLC with a Superose 6 column, and 0.5-mL fractions were collected for the analysis of (A) cholesterol and (B) TG contents in each by respective assay kits. Abbreviations: Tg, transgenic; WT, wild-type.
Fig. 5
Fig. 5
Cyp7a1-tg mice showed improved insulin sensitivity and glucose homeostasis. Female mice were fed either a chow or Western diet for 4 months. (A) Fasting serum glucose and (B) fasting serum insulin were determined. (C) GTT. (D) ITT. (E,F) Hepatic mRNA expression in mice fasted overnight. Results are expressed as means and standard errors (n =6–12). *Statistical significance (P < 0.05) versus WT mice on a chow diet; **statistically significant difference (P < 0.05) versus HFD-fed WT mice. Abbreviations: GTT, glucose tolerance test; ITT, insulin tolerance test; Tg, transgenic; WT, wild-type.
Fig. 6
Fig. 6
Cyp7a1-tg mice showed increased hepatic glycogen storage. (A) Quantification of the hepatic glycogen content in overnight fasted female mice. (B) Female mice were fed chow or an HFD for 4 months. Hepatic glycogen was determined by PAS staining of liver sections from female mice fasted overnight. (C) Female mice on an HFD were fasted for 16 hours and refed for 6 hours. AKT was immunoprecipitated from pooled liver samples (n =6); total and phosphorylated AKT was detected by WB. (D) Hepatic GSK3β and phosphorylated GSK3β were detected by WB in pooled liver samples (n =6) from refed mice. Results are expressed as means and standard errors (n =6–8). *Statistical significance (P < 0.05) versus WT mice on a chow diet; **statistically significant difference (P < 0.05) versus HFD-fed WT mice. Abbreviations: IP, immunoprecipitation; Tg, transgenic; WB, western blotting; WT, wild-type.
Fig. 7
Fig. 7
Indirect calorimetry analysis of energy expenditure in Cyp7a1-tg mice. Female mice were fed either chow or an HFD for 2 months. (A) O2 consumption and CO2 production were determined in free-fed mice over a period of 24 hours by indirect calorimetry (n =4). For the time, a solid bar indicates the dark cycle, and an open bar indicates the light cycle. The left panel shows VO2, the middle panel shows VCO2, and the right panel shows RQ. (B) The brown adipose mass was determined in female mice fed an HFD (n =6). (C) Female mice on an HFD were refed for 6 hours after 16 hours of fasting, and mRNA expression was measured by real-time PCR (n = 6). Results are expressed as means and standard errors. *Statistically significant difference (P < 0.05) versus WT mice on an HFD. Abbreviations: BW, body weight; CPT1, carnitine palmitoyltransferase 1; Dio2, type 2 deiodinase; PGC1α, peroxisome proliferator-activated receptor γ coactivator-1α; PPARα, peroxisome proliferator-activated receptor α; Tg, transgenic; WT, wild-type.
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