Deficiency of calcium-independent phospholipase A2 beta with aging causes biliary epithelial ductular reaction associated with increased bile acids in enterohepatic circulation

Background/Aims: Calcium-independent phospholipase A2 beta (iPLA2beta) generates lysophosphatidylcholine which is recognized as a macrophage 'fine me' signal for removal of apoptotic cells. We have shown that iPLA2beta deficiency causes an accumulation of apoptotic hepatocytes associated with a decrease of serum and hepatic lipids including cholesterol. We here determined whether iPLA2beta deficiency in aged mice can result in abnormalities in the hepatobiliary system and the alterations of bile acid contents. Methods: Control (WT) and whole body male iPLA2beta-/- mice at 19 – 22 months old were used. Bile acid profiles were measured by liquid-chromatography mass spectrometry. Functional assays included qRT-PCR, histology, and immunohistochemistry (IHC). Results: Livers of aged iPLA2beta-/- mice exhibited increased IHC staining of α-smooth muscle actin and biliary epithelial marker cytokeratin 19 compared with those of aged WT mice. This was concomitant with increases of total, hydrophilic, hydrophobic and secondary bile acids in the bile. The increases of hydrophobic secondary bile acids such as deoxycholic and chenodeoxycholic acids were observed in liver and intestine of iPLA2beta-/- mice, which was associated with increased mRNA expression of CYP7A1 and CYP8B1, and decreased expression of bile acid export genes BSEP and MRP3 in liver as well as OSTα and OSTβ in intestine. In the feces of mutant mice, we observed an increase of deoxycholic acid (suggesting increased dehydroxylation by luminal bacteria), but decreases of tauro-ursodeoxycholic acid as well as tauro- and glyco-chenodeoxycholic acids (suggesting increased deconjugation by luminal bacteria). Conclusions: iPLA2beta deficiency in aged mice caused biliary ductular expansion, and an accumulation of bile acids within enterohepatic circulation. This accumulation was a result of suppressed hepatic and intestinal bile acid export and increased bile acid syntheses, and the latter may lead to a decreased level of the bile acid precursor cholesterol. Thus, iPLA2beta plays a homeostatic role by regulating hepatic bile acid metabolism affecting systemic cholesterol levels and intestinal bile acid contents.

Corresponding author: Chamulitrat, Walee

E-Mail: [e-mail]