Mechanisms for increased expression of cholesterol 7α-hydroxylase (Cyp7a1) in lactating rats

Abstract

Cholesterol 7␣-hydroxylase (Cyp7a1) and the bile acid pool size are increased 2 to 3-fold in lactating postpartum rats. We investigated the interaction of nuclear receptors with the Cyp7a1 proximal promoter and the expression of regulatory signaling pathways in postpartum rats at day 10 (PPd10) versus female controls to identify the mechanisms of increased expression of Cyp7a1, which is maximal at 16 hours. Liver X receptor (LXR␣) and RNA polymerase II (RNA Pol II) recruitment to Cyp7a1 chromatin were increased 1.5-and 2.5-fold, respectively, at 16 hours on PPd10. Expression of nuclear receptors farnesoid X receptor (FXR), LXR␣, liver receptor homolog (LRH-1), hepatocyte nuclear factor 4␣ (HNF4␣), and short heterodimer partner ( C holesterol 7␣-hydroxylase (Cyp7a1) catalyzes the rate-limiting step of the classical pathway of bile acid synthesis and is the major mechanism for cholesterol catabolism and removal from the body. 1 Bile acids form mixed micelles with phospholipids and cholesterol in bile, which is essential for both the absorption and biliary excretion of cholesterol. Rodent Cyp7a1 expression increases in response to cholesterol-enriched diets, [2][3][4] resulting in increased bile acid synthesis, whereas feedback inhibition prevents the accumulation of cytotoxic hydrophobic bile acids. The regulation of Cyp7a1 expression is thus critical for maintenance of cholesterol and bile acid homeostasis.Several nuclear receptors activate transcription of Cyp7a1. Liver X receptor alpha (LXR␣) binds to LXR response elements in the proximal rat 5,6 and mouse 7

Changes in the expression of hepatic genes involved in cholesterol homeostasis in dairy cows in the transition period and at different stages of lactation

“…To our knowledge, the expression of LXRα and its genes involved in bile acid synthesis and cholesterol export in dairy cows during lactation has not yet been investigated in other studies. The results of this study, however, are well in agreement with studies in rats, which also found an increased expression or activity of CYP7A1 in the liver during lactation (Smith et al, 1998;Wooton-Kee et al, 2010;Athippozhy et al, 2011). The upregulation of CYP7A1 has been attributed to an increased recruitment of LXRα, which is in agreement with the present findings, and to a decreased expression of FGF15 and phosphorylated Erk1/2, which are acting as CYP7A1 repressive pathways (Wooton-Kee et al, 2010).…”

Proteasome inhibition protects against diet-induced gallstone formation through modulation of cholesterol and bile acid homeostasis

“…as mitogen-activated protein kinase (maPK) has also been shown to regulate Cyp7a1 transcription (22)(23)(24), the phosphorylation of p38, erK and jnK was examined in livers treated with proteasome inhibitors. Hepatic phosphorylation of jnK and erK, but not p38, was elevated upon administration of Bt and cf ( fig.…”

Protective Effects of Alisol B 23-Acetate Via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Estrogen-Induced Cholestatic Liver Injury in Mice

“…FXR has been reported to play a critical role in bile acid homeostasis (7)(8)(9). FXR activation transiently induces the expression of small heterodimer partner (Shp) and fibroblast growth factor 15 (Fgf15) in mice, and elevated levels of Shp and Fgf15 in turn lead to transcriptional repression of genes involved in bile acid synthesis (10,11). In addition, FXR can down-regulate Na + /taurocholate cotransporting polypeptide (Ntcp), which prevents bile acids uptake into hepatocytes, and induce expression of bile salt export pump (Bsep), which increases bile acid efflux from the liver into bile.…”