title: Characterization of a Novel Intestinal Glycerol-3-phosphate Acyltransferase Pathway and Its Role in Lipid Homeostasis.
abstract: Dietary triglycerides (TG) are absorbed by the enterocytes of the small intestine after luminal hydrolysis into monacylglycerol and fatty acids. Before secretion on chylomicrons, these lipids are reesterified into TG, primarily through the monoacylglycerol pathway. However, targeted deletion of the primary murine monoacylglycerol acyltransferase does not quantitatively affect lipid absorption, suggesting the existence of alternative pathways. Therefore, we investigated the role of the glycerol 3-phosphate pathway in dietary lipid absorption. The expression of glycerol-3-phosphate acyltransferase (GPAT3) was examined throughout the small intestine. To evaluate the role for GPAT3 in lipid absorption, mice harboring a disrupted GPAT3 gene (Gpat3(-/-)) were subjected to an oral lipid challenge and fed a Western-type diet to characterize the role in lipid and cholesterol homeostasis. Additional mechanistic studies were performed in primary enterocytes. GPAT3 was abundantly expressed in the apical surface of enterocytes in the small intestine. After an oral lipid bolus, Gpat3(-/-) mice exhibited attenuated plasma TG excursion and accumulated lipid in the enterocytes. Electron microscopy studies revealed a lack of lipids in the lamina propria and intercellular space in Gpat3(-/-) mice. Gpat3(-/-) enterocytes displayed a compensatory increase in the synthesis of phospholipid and cholesteryl ester. When fed a Western-type diet, hepatic TG and cholesteryl ester accumulation was significantly higher in Gpat3(-/-) mice compared with the wild-type mice accompanied by elevated levels of alanine aminotransferase, a marker of liver injury. Dysregulation of bile acid metabolism was also evident in Gpat3-null mice. These studies identify GPAT3 as a novel enzyme involved in intestinal lipid metabolism.
authors.affiliation: From the Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139 and.
authors.forename: Irani
authors.identifier: http://orcid.org/0000-0002-0500-6247
authors.initials: I
authors.lastname: Khatun
authors.affiliation: From the Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139 and.
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Clark
authors.affiliation: From the Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139 and.
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Vera
authors.affiliation: From the Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139 and.
authors.forename: Kou
authors.initials: K
authors.lastname: Kou
authors.affiliation: From the Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139 and.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Erion
authors.affiliation: Drug Safety Research and Development, Pfizer Worldwide Research and Development, Groton, Connecticut 06340.
authors.forename: Timothy
authors.initials: T
authors.lastname: Coskran
authors.affiliation: Drug Safety Research and Development, Pfizer Worldwide Research and Development, Groton, Connecticut 06340.
authors.forename: Walter F
authors.initials: WF
authors.lastname: Bobrowski
authors.affiliation: Drug Safety Research and Development, Pfizer Worldwide Research and Development, Groton, Connecticut 06340.
authors.forename: Carlin
authors.initials: C
authors.lastname: Okerberg
authors.affiliation: From the Cardiovascular and Metabolic Diseases Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139 and bryan.goodwin@pfizer.com.
authors.forename: Bryan
authors.initials: B
authors.lastname: Goodwin
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D004041:Dietary Fats / Q000494:pharmacology*; D020895:Enterocytes / Q000201:enzymology*; D050356:Lipid Metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010743:Phospholipids / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000494:pharmacology*
chemical_list: D001647:Bile Acids and Salts; D004041:Dietary Fats; D010743:Phospholipids; D014280:Triglycerides; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C000602679:GPAT3 protein, mouse
keywords: chylomicrons; fatty acid; glycerol-3-phosphate acyltransferase; intestinal metabolism; intestine; lipid absorption; lipid transport; triglycerides