RNA sequencing of livers of adult MAPL KO and control mice.
Mitochondrial and peroxisomal anchored protein ligase (MAPL) is a dual ubiquitin and small ubiquitin-like modifier (SUMO) ligase with context-dependent roles in mitochondrial quality control, cell death and inflammation in cultured cell lines. Here, we show that physiological MAPL function in organismal context converges on metabolic control, as knockout mice are viable, but lean, highly insulin sensitive, and protected from high fat-diet induced obesity. MAPL loss leads to liver-specific activation of the integrated stress response, inducing secretion of starvation hormone FGF21, known to drive the reduction of white fat stores and promote insulin sensitivity. During aging, MAPL knockout mice developed fully penetrant spontaneous hepatocellular carcinoma, which is pathologically distinct from NASH/NAFLD-linked liver cancers. Mechanistically, proximity interaction analysis revealed the peroxisomal bile acid transporter ABCD3 (PMP70) as a primary MAPL interacting partner, 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 central regulator of bile acid synthesis whose loss led to the profound disruption of bile acid feedback mechanisms. The unique metabolic consequences of MAPL loss in liver, along with evidence of tumor suppression through the regulation of cell survival pathways, lead ultimately to a new animal model of spontaneous hepatocellular carcinoma. Overall design: For differential expression analysis, transcriptomes of MAPL KO mice were comared to corresponding control mice. Comparisons were made separately for females and males.