期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 13, 期 594, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abd1869
关键词
-
资金
- Department of Medicine at UCLA, pilot grants [P30 DK 41301, P50 AA011999, UL1TR001881, P30 DK063491, P30 DK046200, NIH-1R01AA026914-01A1]
- Canadian Diabetes Association
- AbbVie
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Genome Canada
- Janssen
- Merck KGaA
- Merck Co.
- Novartis
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Innovative Medicines Initiative Joint Undertaking ULTRA-DD [115766]
- Wellcome Trust [106169/Z/14/Z]
- NIH [P30 DK063491, 1R35GM135175-01, R01 DK109724]
- [NIH-1R15GM131289-01]
- [NIH-P01HL028481]
- [DK120342]
- [K99 DK120875]
- [AHA18POST33990256]
This study uncovers the significant role of bilirubin in hepatic insulin resistance and nonalcoholic fatty liver disease development, and reveals ABCB10 as a mitochondrial biliverdin exporter that regulates bilirubin regeneration and intracellular hydrogen peroxide scavenging. The findings demonstrate a maladaptive role of ABCB10-driven bilirubin synthesis in exacerbating insulin resistance and steatosis in obesity, offering potential therapeutic targets for metabolic disorders.
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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