التفاصيل البيبلوغرافية
| العنوان: |
MAPL loss dysregulates bile and liver metabolism in mice. |
| المؤلفون: |
Goyon, Vanessa, Besse‐Patin, Aurèle, Zunino, Rodolfo, Ignatenko, Olesia, Nguyen, Mai, Coyaud, Étienne, Lee, Jonathan M, Nguyen, Bich N, Raught, Brian, McBride, Heidi M |
| المصدر: |
EMBO Reports; 12/6/2023, Vol. 24 Issue 12, p1-27, 27p |
| مستخلص: |
Mitochondrial and peroxisomal anchored protein ligase (MAPL) is a dual ubiquitin and small ubiquitin‐like modifier (SUMO) ligase with roles in mitochondrial quality control, cell death and inflammation in cultured cells. Here, we show that MAPL function in the organismal context converges on metabolic control, as knockout mice are viable, insulin‐sensitive, and protected from diet‐induced obesity. MAPL loss leads to liver‐specific activation of the integrated stress response, inducing secretion of stress hormone FGF21. MAPL knockout mice develop fully penetrant spontaneous hepatocellular carcinoma. Mechanistically, the peroxisomal bile acid transporter ABCD3 is a primary MAPL interacting partner and SUMOylated in a MAPL‐dependent manner. MAPL knockout leads to increased bile acid production coupled with defective regulatory feedback in liver in vivo and in isolated primary hepatocytes, suggesting cell‐autonomous function. Together, our findings establish MAPL function as a regulator of bile acid synthesis whose loss leads to the disruption of bile acid feedback mechanisms. The consequences of MAPL loss in liver, along with evidence of tumor suppression through regulation of cell survival pathways, ultimately lead to hepatocellular carcinogenesis. Synopsis: Mitochondrial and peroxisomal anchored protein ligase (MAPL) deficiency in mice leads to loss of SUMOylation of the peroxisomal bile acid transporter ABCD3 and defects in the bile acid metabolism. MAPL knockout mice develop liver stress and spontaneous hepatocellular carcinoma.ABCD3 is SUMOylated by MAPL.MAPL knockout mice exhibit increased bile flux and secretion from the liver.MAPL deficiency leads to liver‐specific activation of the integrated stress response.MAPL‐deficient hepatocytes are protected from genotoxic stress‐induced cell death.MAPL knockout mice develop fully penetrant spontaneous hepatocellular carcinoma. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
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