Mice with hyperbilirubinemia due to Gilbert’s syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARα

Abstract

Gilbert's syndrome in humans is derived from a polymorphism (TA repeat) in the hepatic gene that results in decreased conjugation and increased levels of unconjugated bilirubin. Recently, we have shown that bilirubin binds directly to the fat-burning nuclear peroxisome proliferator-activated receptor-α (PPARα). Additionally, we have shown that serine 73 phosphorylation [Ser(P)] of PPARα decreases activity by reducing its protein levels and transcriptional activity. The aim of this study was to determine whether humanized mice with the Gilbert's polymorphism (HuUGT*28) have increased PPARα activation and reduced hepatic fat accumulation. To determine whether humanized mice with Gilbert's mutation (HuUGT*28) have reduced hepatic lipids, we placed them and C57BL/6J control mice on a high-fat (60%) diet for 36 wk. Body weights, fat and lean mass, and fasting blood glucose and insulin levels were measured every 6 wk throughout the investigation. At the end of the study, hepatic lipid content was measured and PPARα regulated genes as well as immunostaining of Ser(P) PPARα from liver sections. The HuUGT*28 mice had increased serum bilirubin, lean body mass, decreased fat mass, and hepatic lipid content as well as lower serum glucose and insulin levels. Also, the HuUGT*28 mice had reduced Ser(P) PPARα immunostaining in livers and increased PPARα transcriptional activity compared with controls. A chronic but mild endogenous increase in unconjugated hyperbiliubinemia protects against hepatic steatosis through a reduction in Ser(P) PPARα, causing an increase in PPARα transcriptional activity.

Biliverdin Reductase A (BVRA) Knockout in Adipocytes Induces Hypertrophy and Reduces Mitochondria in White Fat of Obese Mice

“…We have previously demonstrated that hepatocyte-specific loss of BVRA results in exacerbation of hepatic steatosis and insulin resistance in response to a chronic HFD through alterations in PPARα [21]. Activation of heme oxygenase-1 (HO-1) has beneficial effects to prevent fatty liver disease [15,31,70,71], which is most likely mediated by BVRA production of bilirubin [15,21,28,72]. Others have shown that heme-derived metabolic signals dictate immune responses [21].…”

“…Samples were collected under light isoflurane anesthesia via the orbital sinus. The fasting glucose levels were measured using an Accu-Chek Advantage glucometer (Roche, Mannheim, Germany) and fasting insulin levels were measured by ELISA (Ultrasensitive Mouse Insulin Kit, Crystal Chem, Elk Grove Village, IL, USA) as previously described [22,26,[28][29][30][31].…”

Induction of Mild Hyperbilirubinemia: Hype or Real Therapeutic Opportunity?

“…Bilirubin was recently reported to act as a ligand for the peroxisome proliferator-activated receptor-alpha increasing its transcriptional activity. 11 This may have possible clinical relevance because the protection from high-fat diet-induced hepatic steatosis and insulin resistance due to increased peroxisome proliferatoractivated receptor-alpha activity were reported on the novel GS mouse model. 11 Based on these observations, bilirubin seems to act as a real endocrine molecule.…”

“…Although toxic concentrations of bilirubin induce ER stress, milder elevations of bilirubin concentrations attenuate ER stress. Bilirubin was recently reported to act as a ligand for the peroxisome proliferator‐activated receptor‐alpha increasing its transcriptional activity . This may have possible clinical relevance because the protection from high‐fat diet–induced hepatic steatosis and insulin resistance due to increased peroxisome proliferator‐activated receptor‐alpha activity were reported on the novel GS mouse model .…”

Deciphering the Roles of Thiazolidinediones and PPARγin Bladder Cancer

“…Once activated, PPAR α regulates genes that encode for mitochondrial and peroxisomal β -oxidation, which reduces dyslipidemia. In addition, activated PPAR α functions to hinder hepatic fatty acid synthesis through inhibition of FAS and SREBP1 and therefore lower lipid levels [21, 79, 80]. Dual agonists are a class of drugs that activate both PPAR α and PPAR γ , thereby combating diabetes mellitus and the metabolic syndrome among patients diagnosed with both conditions [81].…”