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Role of phosphodiesterase 8A (PDE8A) in lipid metabolism in the liver
Author(s) -
ShimizuAlbergine Masami,
Patrucco Enrico,
Tsai Lisa,
Campbell Jean S.,
Beavo Joseph A.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.909.4
Subject(s) - creb , lipid metabolism , endocrinology , medicine , phosphodiesterase , creb1 , chemistry , adenylyl cyclase , protein kinase a , phosphorylation , cyclic nucleotide phosphodiesterase , lipid droplet , signal transduction , biology , biochemistry , enzyme , transcription factor , gene
The liver plays a pivotal role in lipid metabolism. Storage of lipids in hepatocytes is used as a means of energy preservation. However, an excess accumulation of neutral lipids in hepatocytes is often a sign of obesity, insulin resistance and type2 diabetes. Intracellular cyclic AMP levels are tightly regulated by cyclic nucleotide phosphodiesterases (PDEs) as well as its formation through the activation of adenylyl cyclase. Recent studies have demonstrated that inhibition of the cyclic AMP response element‐binding protein CREB, one mediator of cyclic AMP signaling pathways, causes increased hepatic triglyceride content, leading to a fatty liver phenotype (Herzig et al., Nature 426:190 (2003)). This study suggests that cyclic AMP/CREB pathway might regulate lipid metabolism in the liver. We have observed that PDE8A, a newly identified cAMP‐specific PDE isoform, is expressed in hepatocytes. Under fasting condition, triglyceride levels were increased in the liver of wild‐type mice, but this increase is abolished in PDE8A knockout mice. This data suggests that higher cyclic AMP levels in a compartment regulated by PDE8A can have a negative effect on lipid accumulation either through decreased lipid synthesis and/or increased lipid breakdown. We also find that hormone stimulated hepatocytes isolated from PDE8A knockout mice showed higher levels of PKA‐dependent protein phosphorylation compared to the wild‐type cells. Therefore, we speculate that the lipid accumulation in the liver is modulated by cAMP‐dependent processes that are regulated by PDE8A. Supported by NIH grant DK21723.