It is well known that cholesterol synthesis increases during the postprandial state to meet increasing demands for cholesterol.[19] We recently reported that feeding rapidly and markedly induced CYP7A1 mRNA expression and increased CYP7A1 enzyme activity by ∼2-fold in mice.[15] Furthermore, CYP7A1 mRNA expression peaked 3 hours after refeeding, whereas HMG-CoA reductase mRNA was minimally affected at 3 hours, but increased by ∼12-fold

6 hours after refeeding.[15] We hypothesize that rapid nutritional induction of CYP7A1 may play a role in stimulating postprandial cholesterol synthesis and selleck lipid homeostasis. Upon food intake, bile acids released into the intestine induce fibroblast growth factor 15, which may be transported to hepatocytes to inhibit bile acid synthesis.[20] This mechanism may reduce CYP7A1 to basal levels after the postprandial period. Postprandial increase in bile acid synthesis is also supported by a recent report that serum bile acid concentrations increased after oral glucose challenge in patients with normal glucose tolerance, but this response was blunted

in patients with impaired glucose tolerance.[21] Interestingly, Roux-en-Y gastric bypass rapidly improved IR and glucose tolerance and is associated with higher serum bile acid levels.[22, 23] Pictilisib concentration Reduced bile acid circulation back to the liver in bypass patients may stimulate bile acid synthesis and signaling, which stimulates energy metabolism and glucagon-like Rucaparib purchase peptide

1 to improve insulin sensitivity and reduce weight. This study unexpectedly revealed that marked induction of CYP7A1 enzyme activity in mouse liver resulted in dissociation of SREBP1c-dependent lipogenic gene expression and hepatic fatty acid synthesis rate. Increased SREBP1c and its targets, FAS and ACC, in Cyp7a1-tg mice (despite a 2-fold to 3-fold enlarged bile acid pool) suggests that CYP7A1 enzyme activity, presumably by modulating cholesterol catabolism, may have a predominant role in SREBP1c maturation over the repressive effect of bile acids on SREBP1c-regulated lipogenesis. Furthermore, these results suggest that reduced hepatic fatty acid synthesis rate in Cyp7a1-tg mice is unlikely a direct result of transcriptional repression of hepatic lipogenic genes by the bile acid/FXR/SHP pathway, as previously reported.[24] Circulating bile acids modulate peripheral energy expenditure, which could indirectly affect hepatic lipogenesis in Cyp7a1-tg mice.[6, 25] Our results here support such a mechanism that stimulation of bile acid and cholesterol synthesis could have a negative effect on de novo lipogenesis by limiting cellular acetyl-CoA availability for fatty acid synthesis.