Research ArticleMetabolism

ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity

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Science Translational Medicine  19 May 2021:
Vol. 13, Issue 594, eabd1869
DOI: 10.1126/scitranslmed.abd1869

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Heme homeostasis

Mitochondrial membrane transporter ABCB10 has been linked to heme metabolism, but its exact function is unclear. Shum et al. show in mouse and human primary hepatocytes that ABCB10 transports biliverdin out of the mitochondria to further supply synthesis of heme metabolite bilirubin. ABCB10 liver-specific knockout mice showed enhanced mitochondrial respiration and were protected from diet-induced obesity, insulin resistance, and hepatic steatosis, which the authors in part tied to the modulation of a regulatory phosphatase upon the resulting oxidative shift. Overexpression of ABCB10 impaired insulin signaling in hepatocytes in vitro and mice on a high-fat diet expressed increased ABCB10 in the liver, implying maladaptive potential of the transporter in obesity.

Abstract

Although the role of hydrophilic antioxidants in the development of hepatic insulin resistance and nonalcoholic fatty liver disease has been well studied, the role of lipophilic antioxidants remains poorly characterized. A known lipophilic hydrogen peroxide scavenger is bilirubin, which can be oxidized to biliverdin and then reduced back to bilirubin by cytosolic biliverdin reductase. Oxidation of bilirubin to biliverdin inside mitochondria must be followed by the export of biliverdin to the cytosol, where biliverdin is reduced back to bilirubin. Thus, the putative mitochondrial exporter of biliverdin is expected to be a major determinant of bilirubin regeneration and intracellular hydrogen peroxide scavenging. Here, we identified ABCB10 as a mitochondrial biliverdin exporter. ABCB10 reconstituted into liposomes transported biliverdin, and ABCB10 deletion caused accumulation of biliverdin inside mitochondria. Obesity with insulin resistance up-regulated hepatic ABCB10 expression in mice and elevated cytosolic and mitochondrial bilirubin content in an ABCB10-dependent manner. Revealing a maladaptive role of ABCB10-driven bilirubin synthesis, hepatic ABCB10 deletion protected diet-induced obese mice from steatosis and hyperglycemia, improving insulin-mediated suppression of glucose production and decreasing lipogenic SREBP-1c expression. Protection was concurrent with enhanced mitochondrial function and increased inactivation of PTP1B, a phosphatase disrupting insulin signaling and elevating SREBP-1c expression. Restoration of cellular bilirubin content in ABCB10 KO hepatocytes reversed the improvements in mitochondrial function and PTP1B inactivation, demonstrating that bilirubin was the maladaptive effector linked to ABCB10 function. Thus, we identified a fundamental transport process that amplifies intracellular bilirubin redox actions, which can exacerbate insulin resistance and steatosis in obesity.

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