Elevated levels of cholesterol and fatty acid synthesis may be responsible for the accumulation of lipids in the
liver. The rate-limiting enzymes for cholesterol synthesis are HMG-CoA synthase 1 (HMGCS1) and HMG-CoA reductase (HMGCR). We found that the hepatic mRNA expression levels of these enzymes were in fact down-regulated in PLA2GXIIB−/− compared to PLA2GXIIB+/+ mice (Supporting Information Fig. 3A). Additionally, the mRNA expression levels of fatty acid synthase (FASN) and stearoyl CoA desaturase-1 (SCD1), two key enzymes for fatty acid synthesis, were also down-regulated in the liver of PLA2GXIIB−/− (Supporting Information Fig. 3A). The reduced expression levels of these genes are likely to be a result of a negative feedback mechanism in response to elevated levels of hepatic find more lipids. Consistently, the expression levels of several fatty acid transport
proteins (FATP) were also reduced (Supporting Information Fig. 3B). In contrast, the expression levels of several genes involved in fatty acid β-oxidation were not significantly altered www.selleckchem.com/products/pifithrin-alpha.html (Supporting Information Fig. 3C). Therefore, alterations in lipid synthesis, transport, and catabolism are unlikely to be responsible for the fatty liver phenotype in PLA2GXIIB-null mice. Hepatic secretion of TGs and cholesterol in the form of VLDL-TG is responsible for transporting endogenous lipids into the serum. We next investigated if defects in this pathway are responsible for the accumulation of lipids in the liver. After an intravenous injection of Triton WR1339, which blocks the catabolism of VLDL, the rate of serum TG accumulation was measured by determining TG levels in the serum at appropriate time points (Fig. 5A). The ADP ribosylation factor TG accumulation rate calculated for each individual mouse was normalized
to its body weight. The secretion rate was calculated from the slope of the individual lines and expressed as millimole/kilogram/hour (Fig. 5B). PLA2GXIIB−/− mice showed an approximately 50% reduction in VLDL-TG secretion (Figs. 5A and 6B). Because each VLDL particle contains one molecule of apolipoprotein B (ApoB), using an antibody that recognizes both ApoB100 and its processed form ApoB48, we found that ApoB100 within the VLDL fraction was significantly reduced whereas ApoB48 was selectively less affected in PLA2GXIIB−/− mice by western blot analysis (Fig. 5C). Consistently, total serum ApoB level was reduced in PLA2GXIIB−/− mice by an ELISA assay (Fig. 5D); whereas, liver total ApoB level was actually modestly increased (Fig. 5D), strongly suggesting that the secretion of VLDL-TG is defective. To confirm the phenotypes of PLA2GXIIB−/− mice were due to loss of PLA2GXIIB function, we generated an adenovirus encoding PLA2GXIIB.
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