Genetic ablation of Cyp8b1 preserves host metabolic function by repressing steatohepatitis and altering gut microbiota composition
Genetic ablation of Cyp8b1 preserves host metabolic function by repressing steatohepatitis and altering gut microbiota composition
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DOI：
10.1152/ajpendo.00172.2017
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发表时间：
2018-05-01
影响因子：
5.1
通讯作者：
Hayden, Michael R.
中科院分区：
文献类型：
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作者：
Patankar, Jay, V;Wong, Chi K.;Hayden, Michael R.
2型糖尿病(T2D)和非酒精性脂肪性肝炎(NASH)都与肝脏线粒体呼吸能力降低有关。胆酸(CA)是调节肝脏脂质代谢的主要12α-羟基胆汁酸，其循环水平与胰岛素抵抗呈负相关。通过固醇12α-羟基酶(Cyp8bl(-/-))的遗传破坏来取消CA的合成会导致对糖尿病和肝脏脂肪变性的抵抗。在这里，我们发现长期刺激肝脏脂肪生成会导致对照组小鼠(CypSb1(+/+))的整体代谢和呼吸功能严重受损，但在Cyp8b1(-/-)小鼠中却没有。Cyp8bl(-/-)小鼠通过抑制肝脏新生脂基因和蛋白的表达以及改变肠道微生物群组成来保护小鼠免受与T2D和NASH相关的代谢损伤。当NASH诱导与新生脂肪生成(DNL)的损伤无关时，保护性表型受到损害。因此，CypSbl(-/-)小鼠也显示出肝脏炎症和纤维化的减少，以及小肠抗菌动力学的转变。我们的数据表明，Cyp8bl(-/-)小鼠胆汁酸成分的改变通过抑制肝脏DNL并推动肠道抗菌反应的有利变化来保护代谢和呼吸功能。
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.