Role of the G2A Receptor and LXR Phosophorylation in Hepatic Cholesterol Homeostasis

The liver is the central site of cholesterol synthesis and metabolism in the body. Alterations in hepatic cholesterol synthesis pathways can lead to the formation of cholesterol gallstone disease and dyslipidemia. Cholesterol gallstone disease is the most common digestive disease causing hospitalization in the West. Dyslipidemia is a well characterized risk factor for development of atherosclerosis and coronary heart disease, the leading cause of death in the United States. Circulating plasma cholesterol levels are tightly regulated. However, the prevalence of modern Western lifestyles which combine decreased physical activity with increased fat and cholesterol intake has led to a staggering increase in the occurrence of dyslipidemia and is also a risk factor for the development of gallstones. Understanding the molecular pathways controlling hepatic cholesterol homeostasis is an attractive scientific and therapeutic target of inquiry in targeting these pathologies. The G2A receptor is a G-protein coupled receptor implicated in the pathogenesis of atherosclerosis and autoimmune diseases. We observe increased severity and onset of cholesterol gallstone disease in G2A-deficient (G2A-/-) mice fed a lithogenic diet. To further understand the mechanisms underlying this disease phenotype, we isolate livers and bile from G2A-/- mice and find that they have an increased biliary cholesterol saturation index and altered hepatic expression of nuclear receptors and ABC transporters involved in bile formation. Interestingly, we discover that G2A-/- mice have elevated expression of the transcription factor LXR, however transactivation of LXR target genes is impaired. LXR is a whole body sterol sensor regulating the cellular response to cholesterol accumulation. We hypothesize that LXR undergoes a postii translational modification that affects its ability to activate target gene transcription. We find that LXR is hyper-phosphorylated in the livers of G2A-/- mice and in C57BL/6J mice fed a 100r 60 0IO diet. We discover a novel kinase, JNK, capable of phosphorylating LXR in primary hepatocytes. LXR phosphorylation inhibits transcription of downstream target genes. In hepatocytes, we discover that inhibition of JNK-mediated LXR phosphorylation leads to elevated transcription of ABCA1, a protein responsible for efflux of cholesterol to lipid-free ApoA1. A greater understanding of the role of G2A and LXR phosphorylation in hepatic cholesterol regulation could provide important insight into molecular regulation of hepatic cholesterol homeostasis.

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