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Glycosylphosphatidylinositol-Specific Phospholipase D in Nonalcoholic Fatty Liver Disease: A Preliminary Study

Departments of Medicine (N.C., R.V., N.S.R., M.A.D.) and Biochemistry and Molecular Biology (M.A.D.), Indiana University School of Medicine and Department of Veterans Affairs (M.A.D.), Indianapolis, Indiana 46202

Address all correspondence and requests for reprints to: Mark Deeg, M.D., Ph.D., Division of Endocrinology and Metabolism, Indiana University School of Medicine, 1481 West 10th Street, Indianapolis, Indiana 46202. E-mail: mdeeg{at}iupui.edu.

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. ß-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 µg/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.