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Chapter 27: Lipids: Bile Acid Metabolism

The Ayurvedic practice of medicine, native to India, has demonstrated a cholesterol-lowering benefit to the guggul lipid extract from the myrrh tree, guggulsterone. This lipid extract has been shown in laboratory studies to activate the expression of a gene involved in the regulation of bile acid metabolism. Which of the following genes is activated by guggul lipids?

A. 7α-hydroxylase (CYP7A1)

B. farnesoid X receptor (FXR)

C. pregnane X receptor (PXR)

D. multidrug-resistance protein 3 (MDR3)

E. small heterodimer partner (SHP)

Answer C: In the Ayurvedic tradition of medicine, any resin that is collected by tapping the trunk of a tree is called guggul (or guggal). The cholesterol-lowering action of the guggul from the Mukul myrrh tree (Commiphora mukul) of India is that a lipid component of this extract called guggulsterone (also called guggul lipid) is an antagonist to FXR. However, in addition to its effects on FXR function, guggulsterone has been shown to activate the pregnane X receptor (PXR) which is another member of the nuclear receptor superfamily. PXR is a recognized receptor for lithocholic acid and other bile acid precursors. PXR activation leads to repression of bile acid synthesis due to its physical association with hepatocyte nuclear factor 4α (HNF4α) causing this transcription factor to no longer be able to associate with the transcriptional coactivator PGC1α (PPARγ coactivator 1α) which ultimately leads to loss of transcription factor activation of CYP7A1.

A 2-year-old girl who is exhibiting a failure to thrive is diagnosed with hepatic failure and cholestasis. Her pediatrician suspects the girl is suffering from familial intrahepatic cholestasis. Which of the following genes is likely harboring a mutation resulting in the observed symptoms?

A. 7α-hydroxylase (CYP7A1)

B. bile salt export pump (BSEP)

C. farnesoid X receptor (FXR)

D. pregnane X receptor (PXR)

E. sodium (Na+)-taurocholate cotransporting polypeptide (NTCP)

Answer B: BSEP is a member of the ABC family of transporters (BSEP is also identified as ABCB11) and it is involved in the process of exporting bile acids out of hepatocytes thus reducing their toxicity to these cells. Mutation in BSEP is associated with familial intrahepatic cholestasis type 2.

You are measuring bile acid metabolites produced by a cell line isolated from a hepatoma. Mass spec and gas chromatographic studies indicate that the ...

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