The major mechanism for removal of cholesterol is through bile excretion either by direct transport of intact cholesterol to the bile or by conversion into bile acids in the liver, mediated by the enzymes CYP7A1, CYP8B1 and CYP27A1
Recently, Nishikawa et al (22) reported that liver mitochondrial CYP27A1
can catalyse 1[alpha]-hydroxylation of 25-OHD.
La XCT es una enfermedad que afecta a la sintesis de acidos biliares y la causa una mutacion autosomica recesiva en CYP27A1
. Induce trastornos en la enzima mitocondrial P450 esterol 27-hidroxilasa, lo que conlleva una acumulacion de colestanol en varios tejidos viscerales, incluido el cerebro, y la formacion de xantomas (76).
The realization of the biological effects of vitamin D in cells is closely related to the functioning of the vitamin D-endo/para/autocrine system, which includes (1) photoconversion of 7-dehydrocholesterol in the skin with the formation of cholecalciferol; (2) synthesis of 25OHD (calcidiol) in the liver by means of two key vitamin D 25-hydroxylases (cytochromes P450), CYP2R1 and CYP27A1
; (3) conversion of 25-hydroxyvitamin D (25OHD) in the kidneys or extrarenal tissues to hormonally active form, 1[alpha],25[(OH).sub.2]D, by 25OH-1[alpha]-hydroxylase (CYP27B1); (4) calcitriol transport to target organs by vitamin D binding protein (VDBP); and (5) binding of 1[alpha],25[(OH).sub.2]D to vitamin D receptors (VDR) and regulation of gene expression .
It was also associated with the downregulation of genes associated with cholesterol ester formation and the upregulation of carboxyl ester lipase (CEL), cholesterol 25-hydroxylase (CH25H), and sterol 27-hydroxylase (CYP27A1
The CYP27B1 gene showed overexpression in OSCC, while CYP27A1
, CYP2E1, CYP2R1, CYP2J2, CYP2U1, CYP4F12, CYP4X1, CYP4B1, PTGIS, ALOX12B, and MAOB genes showed reduced expression (Table 1 and Figure 2).
The first enzyme in the alternative pathway is mitochondrial sterol-27 hydroxylase (encoded by CYP27A1
gene encodes one of the key enzymes for bile acid synthesis pathways .
During lipid metabolism, (1) TMAO significantly increases the expression of ABCA1 and ABCG1 in the liver which helps cholesterol efflux to apoA1 as the cholesterol acceptor; (2) TMAO in the gut also markedly reduces the mRNA expression of NPC1L1, which transports cholesterol into the enterocyte from the gut lumen; (3) TMAO reduces the bile acid pool in the liver, which is associated with the classic RCT by reducing synthetic enzymes CYP7A1 and CYP27A1
; and (4) TMAO also reduces the expression of ABCG5/8 in the TICE pathway.
Moreover, the levels of bile acid synthetic enzymes (Cyp7a1 and Cyp27a1
) and bile acid transporters (Oatp1, Oatp4, Mrp2, and Ntcp) in the liver were reduced when the mice were provided TMAO.
The expression of mRNAs encoded by other genes, such as Cyp8b1, Cyp27a1
, and Akr1dl, all involved in bile acid synthesis, were not significantly affected by TCDF exposure (Figure 4H).