6D) Enhanced taurolithocholate, which is a potent stimulator of

6D). Enhanced taurolithocholate, which is a potent stimulator of oxidative stress, was lower in the LCA-treated Fxr-null mice as compared to wildtype mice (Supporting Fig. S6A), and hepatic H2O2 levels were lower (Supporting Fig. S6B). Elevated oxidative stress can accelerate hepatic TGF-β activation.35 These results may indicate that oxidative stress-activated TGF-β-SMAD3 signaling is involved in LCA-induced disruption of phospholipid/sphingolipid homeostasis. The current study demonstrated

that LCA disrupted phospholipid and sphingolipid homeostasis following changes in the expression of enzymes involved in their synthesis (Fig. 7). To further determine the global changes Selleck JAK inhibitor of serum metabolites after an LCA diet, the serum metabolome of the LCA-treated mice was interrogated and compared with that of the controls.

UPLC-TOFMS, in conjunction with an OPLS analysis, revealed changes in serum metabolites after LCA exposure, and determined bile acid metabolites as being markedly elevated, whereas LPCs were decreased. Because the liver is the major site of serum LPC biogenesis,36, 37 the changes in serum lipid profiles may reflect liver injury. Levels of the major LPCs in serum (16:0-, 18:0-, 18:1-, and 18:2-LPC) were decreased in a time-dependent manner after LCA Raf inhibitor exposure, and interestingly, serum LPC levels were negatively correlated with serum ALP levels, which is a conventional marker for cholestasis. In addition, the decrease in serum LPC levels was attenuated in Fxr-null mice, which are resistant to LCA-induced liver injury. The LCA-treated Fxr-null mice, however, showed significantly decreased unsaturated LPC (18:1- and 18:2-LPC) as well as the wildtype mice. This is due to lower hepatic SCD1 that produces unsaturated LPC.21 Although the association of hepatic Scd1 expression with biliary injury requires further investigation, these results strongly support the view that LPCs, especially saturated LPCs, reflect the severity of biliary injury such as cholestasis. LPC was reported to be a proinflammatory atherogenic phospholipid

that activates a variety of immune cells such as monocytes and neutrophils.38-41 In immune cells, oxidative stress stimulates LPC production following enhanced PLA2 activity.42 Hydrophobic selleck chemicals bile acid exposure leads to reactive oxygen generation from mitochondria.43 However, LCA exposure did not induce PLA2 activities in either serum or liver, but rather decreased serum LPC levels. Thus, in vivo, especially with regard to hepatic PC metabolism, the influence of bile acid accumulation on PLA2 activity may be marginal. In contrast, LCA exposure induced the expression of Lpcat 1, 2, and 4 genes in livers. In the hepatic remodeling system of PC (Lands’ cycle44), PC production is enhanced after LCA exposure. Despite this, LCA exposure significantly decreased phospholipid levels in bile. An excess of hepatic bile acids can lead to increased consumption of phospholipids to facilitate the excretion of the bile acids.

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