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MAPL loss dysregulates bile and liver metabolism in mice.

ABSTRACT: 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.

SUBMITTER: Goyon V

PROVIDER: S-EPMC10702803 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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MAPL loss dysregulates bile and liver metabolism in mice.

Goyon Vanessa V Besse-Patin Aurèle A Zunino Rodolfo R Ignatenko Olesia O Nguyen Mai M Coyaud Étienne É Lee Jonathan M JM Nguyen Bich N BN Raught Brian B McBride Heidi M HM

EMBO reports 20231114 12

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 ...[more]

PMID: 37962001

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MAPL loss dysregulates bile and liver metabolism in mice.

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MAPL loss dysregulates bile and liver metabolism in mice.

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