Mitochondrial oxysterol biosynthetic pathway gives evidence for CYP7B1 as controller of regulatory oxysterols. Issue 189 (May 2019)

• Record Type: Journal Article
• Authors: Kakiyama, Genta; Marques, Dalila; Takei, Hajime; Nittono, Hiroshi; Erickson, Sandra; Fuchs, Michael; Rodriguez-Agudo, Daniel; Gil, Gregorio; Hylemon, Phillip B.; Zhou, Huiping; Bajaj, Jasmohan S.; Pandak, William M.
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 189(2019)
• Page Start: 36
• Page End: 47
• Publication Date: 2019-05
• Subjects: ApoE apolipoprotein E -- CYP7A1 cholesterol 7α-hydroxylase (Cyp7a1 denotes murine) -- CA cholic acid 3α, 7α, 12α-trihydroxy-5β-cholanoic acid) -- CDCA chenodeoxycholic acid 3α, 7α-dihydroxy-5β-cholanoic acid) -- CYP7B1 oxysterol 7α-hydroxylase (Cyp7b1 denotes murine) -- CYP8B1 sterol 12α-hydroxylase -- CYP27A1 sterol 27-hydroxylase (Cyp27a1 denotes murine) -- CYP39A oxysterol 7α-hydroxylase 2 -- diHC dihydroxycholesterol -- FXR farnesoid X receptor -- HMG-CoA hydroxy-methylglutaryl-CoA reductase -- 24HC 24(S)-hydroxycholesterol -- 25HC 25-hydroxycholesterol -- 26HC (25R)-26-hydroxycholestetol -- HDCA hyodeoxycholic acid 3α, 6α-dihydroxy-5β-cholanoic acid) -- isoDCA isodeoxycholic acid 3β, 12α-dihydroxy-5β-cholanoic acid) -- LCA lithocholic acid (3α-hydroxy-5β-cholanoic acid) -- LXR liver X receptor -- βMCA β-muricholic acid 3α, 6β, 7β-trihydroxy-5β-cholanoic acid) -- MDCA murideoxycholic acid 3α, 6β-dihydroxy-5β-cholanoic acid) -- NAFLD nonalcoholic fatty liver disease -- NASH nonalcoholic steatohepatitis -- NTCP Na+-taurocholate co-transporting polypeptide -- RTqPCR quantitative real-time PCR -- SHP short heterodimer partner -- SREBP-1c sterol regulatory element binding protein-1c -- StarD1 steroidogenic acute regulatory protein; Bile acids and salts -- Cytochrome p450 -- Liver -- Mitochondria -- Non-alcoholic fatty liver disease -- Oxysterols; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2019.01.011
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: Cyp27a1 is capable of metabolizing cholesterol to three vital regulatory oxysterols. A new mitochondrial-initiated hepatic pathway of oxysterol/bile acid synthesis. 24HC is metabolized to bile acids via both Cyp7b1 and an independent pathway. Cyp7b1 is a key regulator of the levels of the Cyp27a1 generated oxysterols. Oxysterols are key mediators of cholesterol and lipid homeostasis. Abstract: The aim of this paper was to more completely study the mitochondrial CYP27A1 initiated acidic pathway of cholesterol metabolism. The mitochondrial CYP27A1 initiated pathway of cholesterol metabolism (acidic pathway) is known to synthesize two well-described vital regulators of cholesterol/lipid homeostasis, (25R)-26-hydroxycholesterol (26HC) and 25-hydroxycholesterol (25HC). Both 26HC and 25HC have been shown to be subsequently 7α-hydroxylated by Cyp7b1; reducing their regulatory abilities and furthering their metabolism to chenodeoxycholic acid (CDCA). Cholesterol delivery into the inner mitochondria membrane, where CYP27A1 is located, is considered the pathway's only rate-limiting step. To further explore the pathway, we increased cholesterol transport into mitochondrial CYP27A1 by selectively increased expression of the gene encoding the steroidogenic acute transport protein (StarD1). StarD1 overexpression led to an unanticipated marked down-regulation of oxysterol 7α-hydroxylase (Cyp7b1), a marked increase in 26HC, and the formation of a third vital regulatory oxysterol, 24( S )-hydroxycholesterol (24HC), in B6/129 mice livers. To explore the further metabolism of 24HC, as well as, 25HC and 26HC, characterizations of oxysterols and bile acids using three murine models (StarD1 overexpression, Cyp7b1 −/−, Cyp27a1 −/− ) and human Hep G2 cells were conducted. This report describes the discovery of a new mitochondrial-initiated pathway of oxysterol/bile acid biosynthesis. Just as importantly, it provides evidence for CYP7B1 as a key regulator of three vital intracellular regulatory oxysterol levels.