期刊
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
卷 314, 期 5, 页码 E418-E432出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00172.2017
关键词
Cyp8b1; FXR; gut microbiota; 12 alpha-hydroxylated bile acids; nonalcoholic hepatic steatosis
资金
- Canadian Institutes of Health Research (CIHR) grant [MOP 106684]
- Natural Sciences and Engineering Research Council (NSERC)
- Pfizer-Ripples of Hope postdoctoral fellowship
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK017047] Funding Source: NIH RePORTER
Both type 2 diabetes (T2D) and nonalcoholic steato-hepatitis (NASH) are associated with reduced hepatic mitochondrial respiratory capacity. Cholic acid (CA) is the predominant 12 alpha-hydroxylated bile acid that regulates hepatic lipid metabolism, and its circulating levels are negatively correlated with insulin resistance. Abolishing CA synthesis via the genetic disruption of the enzyme sterol 12 alpha-hydroxylase (Cyp8bl(-/-)) leads in resistance to diabetes and hepatic steatosis. Here, we show that long-term stimulation of hepatic lipogenesis leads to a severe impairment in overall metabolic and respiratory function in control mice (CypSbl(+/+)) but strikingly not in Cyp8b1(-/-)mice. Cyp8bl(-/-) mice arc protected from such metabolic impairments associated with T2D and NASH by inhibiting hepatic de novo lipogenic gene and protein expression and altering gut microbiota composition. The protective phenotype is compromised when NASH induction is independent of impairment in de novo lipogenesis (DNL). Consequently, CypSbl(-/-) mice also show a reduction in hepatic inflammation and fibrosis along with a shift in antimicrobial dynamics in the small intestine. Our data show that the altered bile acid composition of Cyp8bl(-/-) mice preserves metabolic and respiratory function by repressing hepatic DNL and driving favorable changes in gut antimicrobial responses.
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