Hepatic conversion of cholesterol to primary bile acids (cholic acid + chenodeoxycholic acid). Classic pathway: cholesterol → 7α-hydroxycholesterol via CYP7A1 (rate-limiting, FXR-regulated). Alternative pathway: cholesterol → 27-OH-cholesterol via CYP27A1 (relevant in extrahepatic tissues). Primary bile acids conjugate with glycine or taurine before biliary secretion. In the intestine, bacterial 7α-dehydroxylase converts primary bile acids to secondary (deoxycholic + lithocholic acid). FXR feedback closes the loop: enterohepatic bile acid return → ileal FGF19 → hepatic FXR → CYP7A1 suppression.
Organ Systems
digestive
endocrine
Pathway Steps
cholesterol → 7alpha-hydroxycholesterol — via CYP7A1 — rate-limiting; FXR-regulated. CYP7A1 is the rate-limiting step of the classic (neutral) pathway and the body’s principal route for eliminating cholesterol. It is feedback-repressed by bile acids via FXR→SHP and intestinal FGF15/19 — the mechanism behind bile-acid sequestrants and FXR agonists.
7alpha-hydroxycholesterol → cholic-acid — via multi-step (12α-hydroxylation via CYP8B1 + side-chain oxidation via CYP27A1). 12α-hydroxylation by CYP8B1 commits flux toward cholic acid; CYP8B1 activity sets the cholic:chenodeoxycholic ratio, which tunes intestinal cholesterol/fat absorption and is an emerging metabolic drug target.
7alpha-hydroxycholesterol → chenodeoxycholic-acid — via side-chain oxidation via CYP27A1 (skips CYP8B1). Skipping CYP8B1 yields chenodeoxycholic acid, the most potent endogenous FXR ligand. The alternative (acidic) pathway initiated by mitochondrial CYP27A1 predominates in the fetus and contributes more when CYP7A1 is limited.
Known Modulators
glucosamine (substrate) — glycosaminoglycan synthesis precursor. OA + joint claims; sulfate + HCl salt forms; mixed efficacy data
chondroitin (substrate) — GAG building block. OA + joint; often paired with glucosamine