Cell Metabolism
Volume 15, Issue 5, 2 May 2012, Pages 691-702
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Article
Adiponutrin Functions as a Nutritionally Regulated Lysophosphatidic Acid Acyltransferase

https://doi.org/10.1016/j.cmet.2012.04.008Get rights and content
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Summary

Numerous studies in humans link a nonsynonymous genetic polymorphism (I148M) in adiponutrin (ADPN) to various forms of fatty liver disease and liver cirrhosis. Despite its high clinical relevance, the molecular function of ADPN and the mechanism by which I148M variant affects hepatic metabolism are unclear. Here we show that ADPN promotes cellular lipid synthesis by converting lysophosphatidic acid (LPA) into phosphatidic acid. The ADPN-catalyzed LPA acyltransferase (LPAAT) reaction is specific for LPA and long-chain acyl-CoAs. Wild-type mice receiving a high-sucrose diet exhibit substantial upregulation of Adpn in the liver and a concomitant increase in LPAAT activity. In Adpn-deficient mice, this diet-induced increase in hepatic LPAAT activity is reduced. Notably, the I148M variant of human ADPN exhibits increased LPAAT activity leading to increased cellular lipid accumulation. This gain of function provides a plausible biochemical mechanism for the development of liver steatosis in subjects carrying the I148M variant.

Highlights

► Adiponutrin acts as a lysophosphatidic acid acyltransferase ► I148M variant of ADPN represents a gain-of-function mutation ► Adpn-deficient mice on high-sucrose diet exhibit diminished hepatic LPAAT activity ► Overexpression of I148M-ADPN causes increased FFA incorporation into glycerolipids

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