CONTEXT: Recent studies demonstrated that de novo lipogenesis is increased in patients with nonalcoholic fatty liver disease (NAFLD). Patients with NAFLD also have plasma lipid abnormalities. These lipid abnormalities may in part be related to insulin resistance, which is common in patients with NAFLD. Insulin resistance is associated with alterations in proteins involved in lipid metabolism including glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD), which is involved in triglyceride metabolism. OBJECTIVE: The objective of the study was to determine whether alterations in serum and hepatic levels of GPI-PLD occur in patients with NAFLD. DESIGN AND PATIENTS: We examined the following: 1) levels of serum GPI-PLD in nondiabetics with nonalcoholic steatohepatitis, compared with matched controls; 2) hepatic expression of GPI-PLD mRNA in patients with normal liver or NAFLD; and 3) effect of overexpressing GPI-PLD vs. beta-galactosidase (control) on global gene expression in a human hepatoma cell line. RESULTS: The serum levels of GPI-PLD were significantly higher in patients with nonalcoholic steatohepatitis than in matched controls (119 +/- 24 vs.105 +/- 15 microg/ml, P = 0.047). The hepatic expression of GPI-PLD mRNA was increased nearly 3-fold in NAFLD patients, compared with patients with normal liver (3.1 +/- 2.6 vs. 1.1 +/- 1.0 arbitrary units per microgram total RNA, P = 0.026). Finally, overexpressing GPI-PLD was associated with an increase in de novo lipogenesis genes. CONCLUSIONS: Patients with NAFLD have elevated serum levels and hepatic expression of GPI-PLD, and its overexpression in vitro is associated with increased expression of de novo lipogenesis genes. These results suggest that GPI-PLD may play a role in the pathogenesis of NAFLD and/or its metabolic features and warrants further investigation.
CONTEXT: Recent studies demonstrated that de novo lipogenesis is increased in patients with nonalcoholic fatty liver disease (NAFLD). Patients with NAFLD also have plasma lipid abnormalities. These lipid abnormalities may in part be related to insulin resistance, which is common in patients with NAFLD. Insulin resistance is associated with alterations in proteins involved in lipid metabolism including glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD), which is involved in triglyceride metabolism. OBJECTIVE: The objective of the study was to determine whether alterations in serum and hepatic levels of GPI-PLD occur in patients with NAFLD. DESIGN AND PATIENTS: We examined the following: 1) levels of serum GPI-PLD in nondiabetics with nonalcoholic steatohepatitis, compared with matched controls; 2) hepatic expression of GPI-PLD mRNA in patients with normal liver or NAFLD; and 3) effect of overexpressing GPI-PLD vs. beta-galactosidase (control) on global gene expression in a humanhepatoma cell line. RESULTS: The serum levels of GPI-PLD were significantly higher in patients with nonalcoholic steatohepatitis than in matched controls (119 +/- 24 vs.105 +/- 15 microg/ml, P = 0.047). The hepatic expression of GPI-PLD mRNA was increased nearly 3-fold in NAFLD patients, compared with patients with normal liver (3.1 +/- 2.6 vs. 1.1 +/- 1.0 arbitrary units per microgram total RNA, P = 0.026). Finally, overexpressing GPI-PLD was associated with an increase in de novo lipogenesis genes. CONCLUSIONS:Patients with NAFLD have elevated serum levels and hepatic expression of GPI-PLD, and its overexpression in vitro is associated with increased expression of de novo lipogenesis genes. These results suggest that GPI-PLD may play a role in the pathogenesis of NAFLD and/or its metabolic features and warrants further investigation.
Authors: Jonas B Nielsen; Oren Rom; Ida Surakka; Sarah E Graham; Wei Zhou; Tanmoy Roychowdhury; Lars G Fritsche; Sarah A Gagliano Taliun; Carlo Sidore; Yuhao Liu; Maiken E Gabrielsen; Anne Heidi Skogholt; Brooke Wolford; William Overton; Ying Zhao; Jin Chen; He Zhang; Whitney E Hornsby; Akua Acheampong; Austen Grooms; Amanda Schaefer; Gregory J M Zajac; Luis Villacorta; Jifeng Zhang; Ben Brumpton; Mari Løset; Vivek Rai; Pia R Lundegaard; Morten S Olesen; Kent D Taylor; Nicholette D Palmer; Yii-Der Chen; Seung H Choi; Steven A Lubitz; Patrick T Ellinor; Kathleen C Barnes; Michelle Daya; Nicholas Rafaels; Scott T Weiss; Jessica Lasky-Su; Russell P Tracy; Ramachandran S Vasan; L Adrienne Cupples; Rasika A Mathias; Lisa R Yanek; Lewis C Becker; Patricia A Peyser; Lawrence F Bielak; Jennifer A Smith; Stella Aslibekyan; Bertha A Hidalgo; Donna K Arnett; Marguerite R Irvin; James G Wilson; Solomon K Musani; Adolfo Correa; Stephen S Rich; Xiuqing Guo; Jerome I Rotter; Barbara A Konkle; Jill M Johnsen; Allison E Ashley-Koch; Marilyn J Telen; Vivien A Sheehan; John Blangero; Joanne E Curran; Juan M Peralta; Courtney Montgomery; Wayne H-H Sheu; Ren-Hua Chung; Karen Schwander; Seyed M Nouraie; Victor R Gordeuk; Yingze Zhang; Charles Kooperberg; Alexander P Reiner; Rebecca D Jackson; Eugene R Bleecker; Deborah A Meyers; Xingnan Li; Sayantan Das; Ketian Yu; Jonathon LeFaive; Albert Smith; Tom Blackwell; Daniel Taliun; Sebastian Zollner; Lukas Forer; Sebastian Schoenherr; Christian Fuchsberger; Anita Pandit; Matthew Zawistowski; Sachin Kheterpal; Chad M Brummett; Pradeep Natarajan; David Schlessinger; Seunggeun Lee; Hyun Min Kang; Francesco Cucca; Oddgeir L Holmen; Bjørn O Åsvold; Michael Boehnke; Sekar Kathiresan; Goncalo R Abecasis; Y Eugene Chen; Cristen J Willer; Kristian Hveem Journal: Nat Commun Date: 2020-12-18 Impact factor: 14.919
Authors: Xin Yuan; Dawn Waterworth; John R B Perry; Noha Lim; Kijoung Song; John C Chambers; Weihua Zhang; Peter Vollenweider; Heide Stirnadel; Toby Johnson; Sven Bergmann; Noam D Beckmann; Yun Li; Luigi Ferrucci; David Melzer; Dena Hernandez; Andrew Singleton; James Scott; Paul Elliott; Gerard Waeber; Lon Cardon; Timothy M Frayling; Jaspal S Kooner; Vincent Mooser Journal: Am J Hum Genet Date: 2008-10 Impact factor: 11.025