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

Terry D. Hinds, Peter Hosick, Shujuan Chen, Robert H. Tukey, Michael W. Hankins, Andrea Nestor-Kalinoski, David E. Stec

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13 Citations (Scopus)

Abstract

Gilbert’s syndrome in humans is derived from a polymorphism (TA repeat) in the hepatic UGT1A1 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)73] 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)73 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)73 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)73 PPARα, causing an increase in PPARα transcriptional activity.

Original languageEnglish
Pages (from-to)E244-E252
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume312
Issue number4
DOIs
StatePublished - 1 Apr 2017

Fingerprint

Gilbert Disease
Peroxisome Proliferator-Activated Receptors
Hyperbilirubinemia
Serine
Phosphorylation
Liver
Fats
Bilirubin
Lipids
Insulin
High Fat Diet
Serum
Genes
Blood Glucose
Fasting
Body Weight

Keywords

  • Bilirubin
  • Fatty liver
  • Gilbert’s syndrome
  • Nonalcoholic fatty liver disease
  • Peroxisome proliferator-activated receptor-α

Cite this

Hinds, Terry D. ; Hosick, Peter ; Chen, Shujuan ; Tukey, Robert H. ; Hankins, Michael W. ; Nestor-Kalinoski, Andrea ; Stec, David E. / Mice with hyperbilirubinemia due to Gilbert’s syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARα. In: American Journal of Physiology - Endocrinology and Metabolism. 2017 ; Vol. 312, No. 4. pp. E244-E252.
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abstract = "Gilbert’s syndrome in humans is derived from a polymorphism (TA repeat) in the hepatic UGT1A1 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)73] 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)73 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)73 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)73 PPARα, causing an increase in PPARα transcriptional activity.",
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Mice with hyperbilirubinemia due to Gilbert’s syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARα. / Hinds, Terry D.; Hosick, Peter; Chen, Shujuan; Tukey, Robert H.; Hankins, Michael W.; Nestor-Kalinoski, Andrea; Stec, David E.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 312, No. 4, 01.04.2017, p. E244-E252.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Mice with hyperbilirubinemia due to Gilbert’s syndrome polymorphism are resistant to hepatic steatosis by decreased serine 73 phosphorylation of PPARα

AU - Hinds, Terry D.

AU - Hosick, Peter

AU - Chen, Shujuan

AU - Tukey, Robert H.

AU - Hankins, Michael W.

AU - Nestor-Kalinoski, Andrea

AU - Stec, David E.

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AB - Gilbert’s syndrome in humans is derived from a polymorphism (TA repeat) in the hepatic UGT1A1 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)73] 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)73 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)73 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)73 PPARα, causing an increase in PPARα transcriptional activity.

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KW - Fatty liver

KW - Gilbert’s syndrome

KW - Nonalcoholic fatty liver disease

KW - Peroxisome proliferator-activated receptor-α

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