2023
EMBO Rep. 2023 Nov 14:e57972. doi: 10.15252/embr.202357972. Online ahead of print.
MAPL loss dysregulates bile and liver metabolism in mice
Montreal Neurological Institute, McGill University, Montreal, QC, Canada. Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, ON, Canada. Department of Pathology and Cell Biology, University of Montreal, Montreal, QC, Canada. University of Montreal Health Network, Montreal, QC, Canada.
Service type: Knock-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.
Keywords: MUL1; PMP70; SUMO; hepatocellular carcinoma; peroxisome.
