UCLA

Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are both characterized by altered mitochondrial respiratory capacity, steatosis, increased oxidative stress, and inflammation. ATP-binding cassette B10 (ABCB10) is an inner mitochondrial membrane protein that has been shown to participate in redox protection in hematopoietic cells and cardiomyocytes. While it is highly expressed in the liver, it is unknown if ABCB10 has a role in pathogenesis of NAFLD or ALD. Here I address these gaps in knowledge by first describing ABCB10 transport cargo. We find that ABCB10 exports the heme by-product biliverdin (BV) for subsequent reduction to lipophilic antioxidant bilirubin (BR), confirming the mechanism by which ABCB10 exerts antioxidant activity. Moreover, we find that ABCB10 content is differentially altered in NAFLD versus ALD. Here, I describe how increased hepatic ABCB10 promotes NAFLD by decreasing mitochondrial respiration and promoting redox-mediated insulin resistance, both of which lead to hepatosteatosis. Conversely, severe alcoholic hepatitis in mice and patients results in decreased hepatic ABCB10 content. However, hepatic ABCB10 in both mild alcoholic steatohepatitis (ASH) and severe AH does not exert similar effects on mitochondrial respiration and steatosis as in NAFLD. Here I demonstrate that hepatic ABCB10 is not the pivot point which determines progression of ALD nor is it determinative of hepatic mitochondrial respiratory function in ASH or AH but rather mitigates the formation of hepatotoxic neutrophil extracellular traps (NETs) in severe ALD. Future research understanding the role of ABCB10-mediated BR generation and its role redox signaling/homeostasis can provide novel therapeutic approaches to treating liver disease.

ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesityWhile the impact of hydrophilic antioxidants on hepatic insulin resistance and non-alcoholic fatty liver disease (NAFLD) is well understood, the function of lipophilic antioxidants in these conditions is not as clear. Bilirubin, a lipophilic antioxidant known for scavenging hydrogen peroxide (H2O2), undergoes oxidation to biliverdin within mitochondria. This biliverdin is then exported to the cytosol and reduced back to bilirubin by cytosolic biliverdin reductase (BLVRA). The process of biliverdin export from mitochondria is crucial for the regeneration of bilirubin and its role in intracellular H2O2 scavenging. Our research identified ABCB10 as the transporter responsible for exporting biliverdin from mitochondria. We observed that ABCB10 assists in transporting biliverdin and that its deletion leads to biliverdin build-up inside mitochondria. In mice, obesity and insulin resistance were found to increase ABCB10 expression in the liver, boosting both cytosolic and mitochondrial bilirubin levels in an ABCB10-dependent way. Surprisingly, deleting ABCB10 in the livers of obese mice led to protection against steatosis and high blood sugar. This was accompanied by improved insulin regulation of glucose production and reduced expression of the lipogenic enzyme SREBP-1c. This protective effect correlated with better mitochondrial performance and increased deactivation of PTP1B, an enzyme that interferes with insulin signaling and boosts SREBP-1c expression. Reintroducing bilirubin in ABCB10 knockout hepatocytes negated these beneficial effects, highlighting bilirubin's detrimental role associated with ABCB10 activity. Therefore, we've uncovered a vital transport mechanism that magnifies the effects of intracellular bilirubin in insulin resistance and steatosis during obesity.

The mitochondrial biliverdin exporter ABCB10 mitigates the formation of neutrophil extracellular traps in alcoholic hepatitisEffective treatment for acute liver failure due to alcoholic hepatitis (AH) is currently limited to liver transplantation. AH-affected livers exhibit a distinct molecular pattern, marked by impaired redox metabolism in hepatocytes and the presence of neutrophils that produce myeloperoxidase (MPO) and create neutrophil extracellular traps (NETs). Enhanced NET formation and MPO activity are known to aggravate liver damage in AH, both in mice and as a predictor of poor outcomes in human patients. Understanding the mechanisms that inappropriately trigger NET formation in the liver could lead to new treatments for AH. It remains uncertain if the redox imbalances in AH hepatocytes directly promote NET formation. Our research indicates that in AH, both human and mouse livers show reduced levels of the mitochondrial biliverdin exporter ABCB10, which is essential for producing the ROS-neutralizing agent bilirubin within hepatocytes. We found that increasing ABCB10 expression in the hepatocytes of mice with AH effectively reduced MPO gene expression and histone H3 citrullination, an indicator of NET formation. This anti-inflammatory action appears to be due to ABCB10’s role in lessening ROS-induced effects in the liver. Specifically, increasing ABCB10 activity led to a decrease in hepatic 4-HNE protein adducts without notably impacting mitochondrial fat metabolism or reducing steatosis and hepatocyte death. Therefore, our findings suggest that ABCB10's role in managing ROS within hepatocytes can alleviate the harmful activation of neutrophils to form NETs in AH. Enhancing ABCB10 function in hepatocytes might thus reduce acute liver failure in humans by curbing the inflammatory response triggered by excessive NET formation.