Bilirubin remodels murine white adipose tissue by reshaping mitochondrial activity and the coregulator profile of peroxisome proliferator–activated receptor α

Abstract

Activation of lipid-burning pathways in the fat-storing white adipose tissue (WAT) is a promising strategy to improve metabolic health and reduce obesity, insulin resistance, and type II diabetes. For unknown reasons, bilirubin levels are negatively associated with obesity and diabetes. Here, using mice and an array of approaches, including MRI to assess body composition, biochemical assays to measure bilirubin and fatty acids, MitoTracker-based mitochondrial analysis, immunofluorescence, and high-throughput coregulator analysis, we show that bilirubin functions as a molecular switch for the nuclear receptor transcription factor peroxisome proliferator–activated receptor α (PPARα). Bilirubin exerted its effects by recruiting and dissociating specific coregulators in WAT, driving the expression of PPARα target genes such as uncoupling protein 1 (Ucp1) and adrenoreceptor β 3 (Adrb3). We also found that bilirubin is a selective ligand for PPARα and does not affect the activities of the related proteins PPARγ and PPARδ. We further found that diet-induced obese mice with mild hyperbilirubinemia have reduced WAT size and an increased number of mitochondria, associated with a restructuring of PPARα-binding coregulators. We conclude that bilirubin strongly affects organismal body weight by reshaping the PPARα coregulator profile, remodeling WAT to improve metabolic function, and reducing fat accumulation.

Rats Genetically Selected for High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin by Upregulation of Hepatic Biliverdin Reductase-A (BVRA) and Suppression of UGT1A1

“…These results show that higher aerobic exercise capacity enhanced BVRA and reduced UGT1A1 to elevate bilirubin levels. Bilirubin has been shown to activate the transcriptional activity of the nuclear receptor PPARα for gene regulation [18][19][20]. We found no differences in the PPARα mRNA expression (Ppara) between the HCR and LCR ( Figure 4A).…”

“…The PPARα-target gene Gys2 (glycogen synthase-2) [30,37], was significantly (p < 0.05) higher in the HCR rats, but not the glucose and fat scavenger Cd36 (Figure 5C,D). Bilirubin has been shown to activate the transcriptional activity of the nuclear receptor PPARα for gene regulation [18][19][20]. We found no differences in the PPARα mRNA expression (Ppara) between the HCR and LCR ( Figure 4A).…”

“…The PPARα-target gene Gys2 (glycogen synthase-2) [30,37], was significantly (p < 0.05) higher in the HCR rats, but not the glucose and fat scavenger Cd36 (Figure 5C,D). We have shown that bilirubin activation of PPARα induces mitochondrial function [20], and that mice with the loss of BVRA have reduced mitochondrial function [38]. Therefore, we measured citric acid and acetic acid in the HCR and LCR rats, two metabolites associated with mitochondrial activity [39][40][41].…”

“…It is possible that bilirubin protects muscle fibers from injury induced by exercise, delays the development of fatigue, and promotes recovery by inhibiting the disturbance of mitochondrial function [20,60]. While the effect of bilirubin on muscle tissue fibers is currently not known, we have previously shown that the UGT1A1*28 Gilbert's polymorphism mice on a high-fat diet had greater lean body mass compared to high-fat-fed controls [23].…”

“…We have shown that bilirubin has a hormonal function by binding directly to the fat-burning nuclear receptor PPARα inducing transcriptional activity and gene regulation [18][19][20]. PPARα is induced by fasting [21], which is also when bilirubin is the highest [11][12][13][14].…”