Regulation of cholesterol-7α-hydroxylase: BAREly missing a SHP

Abstract

Cholesterol-7 ␣ -hydroxylase (CYP7A1) regulates the pathway through which cholesterol is converted into bile acids. The unique detergent properties of bile acids are essential for the digestion and intestinal absorption of hydrophobic nutrients. Bile acids have potent toxic properties (e.g., membrane disruption) and there are a plethora of mechanisms to limit their accumulation in blood and tissues. The discovery of farnesoid X receptor (FXR), the nuclear receptor activated specifically by bile acids, has opened new insights into these mechanisms. Bile acid activation of FXR has been shown to repress the expression of CYP7A1 via increasing the expression of small heterodimer partner (SHP), a non-DNA binding protein. The increased abundance of SHP causes it to associate with liver receptor homolog (LRH)-1, an obligate factor required for transcription of CYP7A1. Recent studies show there is an "FXR/ SHP-independent" mechanism that also represses CYP7A1 expression. This "FXR/SHP-independent" pathway involves the interaction of bile acids with liver macrophages (i.e., Kupffer cells), which induces the expression, and secretion of cytokines. These inflammatory cytokines, which include tumor necrosis factor ␣ and interleukin-1 ␤ , act upon liver parenchymal cells causing a rapid repression of the CYP7A1 gene. -

Mouse phenogenomics: The fast track to “systems metabolism”

“…For example, we can input a partial list of genes identified as regulators of cholesterol homeostasis by wet biology (Figure 3A) and then compute a lipid-gene network using statistically significant gene expression correlations found in the liver of a genetical genomic data set from a B6BTBRF2 mouse cross (Figure 3B; www.genenetwork.org). In fitting with prior literature, in this network there are strong genetic interactions between LRH-1 and Cyp7a1, ABCA1 and LXR, and SREBP-2 and LXR (Davis et al [2002] and references within). There are, however, also obvious differences in the placement of these nodes as compared to that derived by wet biology (compare Figures 3A and 3B).…”

Up to date on cholesterol 7 alpha-hydroxylase (CYP7A1) in bile acid synthesis

“…4 ). 28 , 87 , 88 In primary human hepatocytes, CDCA and IL-1β markedly induced c-Jun to suppress CYP7A1 and CYP8B1 expression. 89 , 90 Furthermore, CA feeding induced TNFα and IL-1β, and induction of cytokines was blunted in Jnk − / − mice, suggesting that bile acids may activate the bile acid receptor TGR5 in macrophages and Kupffer cells to stimulate pro-inflammatory cytokine production via the JNK pathway to inhibit CYP7A1 and CYP8B1 gene transcription.…”

“… 20 , 27 Rodents (rats and mice) synthesize more cholesterol, and they clear and catabolize cholesterol to bile acids more efficiently than humans. 28 Mice have higher serum high density lipoprotein (HDL)-cholesterol and very little low density lipoprotein (LDL)-cholesterol compared to humans. Mice also produce 6-hydroxylated muricholic acids as the major primary bile acid in the liver and they produce a larger, more hydrophilic bile acid pool compared to humans.…”

Hepatocyte ATF3 protects against atherosclerosis by regulating HDL and bile acid metabolism

“…2l ) suggests that ATF3 induces CYP7A1 indirectly. The BA receptor farnesoid X receptor (FXR) plays an essential role in inhibition of CYP7A1 expression by up-regulating fibroblast growth factor 15 (FGF15) in the intestine and small heterodimer dimer (SHP) in the liver 48 , 49 . However, ATF3 over-expression induced intestinal Fgf15 expression and did not affect hepatic Shp expression ( Extended Data Fig.…”