ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation 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.

The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease

“…Deletion of the mitochondrial protein ABCB8 selectively in the heart has been shown to cause mitochondrial iron overload, increased ROS production, defects in the cytosolic maturation of Fe–S clusters and cardiomyopathy 162 . Furthermore, iron–sulfur clusters transporter ABCB7, mitochondrial (ABCB7) has a role in mitochondrial iron homeostasis 163 , and ATP-binding cassette subfamily B member 10, mitochondrial (ABCB10) has been shown to regulate the early steps of haem synthesis in mitochondria 164 and can also export biliverdin from mitochondria 165 .…”

Understanding the Logistics for the Distribution of Heme in Cells

“… 181 The use of heme catabolites—biliverdin and bilirubin—as a way of tracking and studying heme biochemistry is also promising and is starting to provide interesting insights into the interplay between the biochemistry of heme and other biological pathways. 182 − 189 …”

“…There are other technological approaches to heme quantification, including the use of the antimalarial 4-aminoquinoline probe and peptide-based fluorescent probes . The use of heme catabolitesbiliverdin and bilirubinas a way of tracking and studying heme biochemistry is also promising and is starting to provide interesting insights into the interplay between the biochemistry of heme and other biological pathways. − …”

FoxO transcription factors in mitochondrial homeostasis

“…Activation of FoxO1 in the liver up-regulates heme oxygenase 1 (Hmox1), which is located in inner mitochondrial membrane and catabolizes mitochondrial heme [ 29 , 53 ], the essential cofactors for redox enzymes on the electron transport chain (ETC), thereby compromising the integrity and function of ETC ( Figure 2A ) [ 29 , 54 ]. Although the subcellular location of biliverdin reductase is arguable and under investigation [ 53 , 55 , 56 ], there is evidence showing that biliverdin reductase may partner with Hmox1 in inner mitochondrial membrane to facilitate heme breakdown (by Hmox1) into biliverdin and then into bilirubin (by biliverdin reductase), thereby interfering with ETC and mitochondrial respiration [ 53 , 56 ]. The ETC deficiency results in a lower NAD/NADH ratio and dampens the NAD-dependent deacetylase Sirt1.…”