Blocking Phosphatidylcholine Synthesis Lowers Levels of Circulating Lipids in Mouse Hyperlipidemia Model

Cardiovascular disease researchers seeking new ways to treat hyperlipidemia found that inhibition of the gene encoding a protein required for biosynthesis of phosphatidylcholine, a major cell membrane component, in a mouse model resulted in decreased levels of lipids (cholesterol, triglyceride, and phospholipid) in circulation.

Investigators at SUNY Downstate Medical Center (Brooklyn, NY, USA) genetically engineered a line of C57BL/6J mice to lack the gene for production of the enzyme LPCAT3 (Lysophosphatidylcholine acyltransferase 3), which is involved in the synthesis of the cell membrane lipid phosphatidylcholine (PC).

The investigators reported in the July 28, 2015, online edition of the journal Gastroenterology that knock-out (KO) mice lacking the LPCAT3 gene survived only three weeks after birth. Oil Red O staining showed that the controls, but not LPCAT3 KO mice, accumulated lipids in the small intestine.

Oral administration of PC and olive oil allowed the LPCAT3 KO mice to survive, with the same body weights as controls, but the KO mice had shorter and wider small-intestinal villi and longer and bigger small intestines. These modifications were associated with reduced intestinal uptake of lipid by the small intestine and reduced plasma levels of cholesterol, phospholipid, and triglyceride.

"Hyperlipidemia, or high levels of lipids, is a common disease and contributes significantly to cardiac related morbidity and mortality," said senior author Dr. Xian-Cheng Jiang, professor of cell biology at SUNY Downstate Medical Center. "Statin drug trials have provided the major evidence for the benefits of a therapy that lowers low density lipoprotein (LDL), the so called "bad cholesterol", and statin therapy is now the mainstay of clinical management of cardiovascular disease. However, there are many instances in which patients do not respond to or cannot tolerate statins. Our study is intended to provide a novel approach to reduce the "bad" lipids in the blood. Although the study was conducted in a mouse model, the outcomes may be applicable to humans."

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