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Bile acid synthesis and conjugation in cholangiocytes
- Bile acid interactions with cholangiocytes

Bile acids, phospholipids and cholesterol are synthesized in a cholangiocarcinoma cell line[85]. Cholangiocytes have also been shown to conjugate bile acids[85]. The contribution of cholangiocyte bile acid synthesis and conjugation to the over all bile acid pool seems minimal since less than 3 percent of the total liver mass is composed of cholangiocytes[86].
Our preliminary data suggests that bile acid synthesis through the alternative (mitochondrial) pathway by cholesterol 27-hydroxylase (Cyp27) maybe important in the regulation of cholesterol transport and prevent cholesterol toxicity due to oxysterols in cholangiocytes[87]. Oxysterols (which increase with a higher cell cholesterol pool) are cytotoxic to smooth muscle and endothelial cells and are potentially carcinogenic.
Oxysterols are present in bile, have been shown to induce cholangiocyte apoptosis and may be carcinogenic in biliary epithelium by increasing expression of COX-2[88]. The mechanisms for preventing oxysterol lipotoxicity in cholangiocytes are unknown. Our preliminary studies show normal rat cholangiocytes express the cholesterol transporters ATP binding cassette subclass A (ABCA1) on the basolateral membrane and Niemann-Pick C1 Like 1 (NPC1L1) on the apical membrane[87,89]. The nuclear receptors involved in sensing lipids liver X receptor b (LXRb) and peroxisome proliferator-activated receptor d (PPARd) and Cyp27 are abundantly expressed in cholangiocytes[87]. Activation of LXRb, PPARd, or both in cholangiocytes induces ABCA1 gene and protein expression and increases basolateral excretion of cholesterol. Added oxysterols activate LXR expression and increase basolateral membrane cholesterol efflux. Elevated bile acid levels decrease CYP27 expression. Cholangiocytes absorption of cholesterol at the apical membrane is dependent on the expression of NPC1L1, a cholesterol transporter recently shown to be required for cholesterol absorption in the intestine. Like ABCA1, NPC1L1 is upregulated by PPARd ligands. We propose that upregulation of CYP27 leads to production of oxysterols, which then activate LXR and cholesterol efflux in cholangiocytes. These studies identify a potential reverse cholesterol transport pathway in cholangiocytes regulated by the cholangiocyte cholesterol and bile acids pools. We propose, like the reverse cholesterol transport involving macrophages, cholesterol or oxysterols taken up from bile by cholangiocytes is released into the circulation return to hepatocytes for elimination. The cholangiocyte reverse cholesterol transport pathway may function to prevent biliary damage due to oxysterols.

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