Question 1

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) 7a-hydroxylase (CYP7A1)
B) farnesoid X receptor (FXR)
C) pregnane X receptor (PXR)
D) multidrug-resistance protein 3 (MDR3)
E) small heterodimer partner (SHP)

pregnane X receptor (PXR)

Accepted Answer

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 4a (HNF4a) causing this transcription factor to no longer be able to associate with the transcriptional coactivator PGC1a (PPARg coactivator 1a) which ultimately leads to loss of transcription factor activation of CYP7A1.

Question 2

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) 7a-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)

bile salt export pump (BSEP)

Accepted Answer

Mutations in the bile salt export pump (BSEP) gene are associated with familial intrahepatic cholestasis, leading to hepatic failure and cholestasis in children.  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.

Question 3

You are measuring bile acid metabolites produced by a cell line isolated from a hepatoma. Mass spec and gas chromatographic studies indicate that the cell line produces chenodeoxycholic acid and related metabolites but does not produce cholic acid nor any metabolites of this compound. Which of the following is the most likely enzyme missing or defective in these cells?

A) 7-dehydrocholesterol reductase (DHC7R)
B) 3b-hydroxy Δ⁵ C₂₇-steroid oxidoreductase (HSD3B7)
C) 7a-hydroxylase (CYP7A1)
D) oxysterol 7a-hydroxylase (CYP7B1)
E) sterol 27-hydroxylase (CYP27A1)

Accepted Answer

CYP7A1 (7a-hydroxylase) is responsible for the conversion of cholesterol to 7a-hydroxycholesterol, a precursor for both chenodeoxycholic acid and cholic acid. If cholic acid is not produced, it suggests a defect in CYP7A1, which is crucial for its synthesis.

Question 4

A 5-month-old infant is brought to her pediatrician because her parents are concerned about her general failure to thrive and a progressive yellowing of her eyes and skin. Upon examination it is noted the infant has slightly bowing legs indicative of rickets, hepatomegaly, poorly clotting blood, and fatty diarrhea. The ricketslike symptoms and the fatty stool are indicative of lipid maladsorption. The pediatrician makes a diagnosis of a bile acid metabolism disorder. Which of the following enzymes is likely to be defective in this infant?

A) bile salt export protein (BSEP)
B) 3b-hydroxy Δ⁵ C₂₇-steroid oxidoreductase (HSD3B7)
C) 7a-hydroxylase (CYP7A1)
D) multidrug-resistance-associated protein 2 (MRP2)
E) sterol 27-hydroxylase (CYP27A1)

Accepted Answer

The symptoms suggest a defect in bile acid synthesis, leading to lipid malabsorption. 3b-hydroxy Δ⁵ C₂₇-steroid oxidoreductase (HSD3B7) is an enzyme involved in the early steps of bile acid synthesis. A defect in this enzyme can lead to the accumulation of toxic intermediates and impaired bile acid production, causing the symptoms observed.

Question 5

You have generated a line of transgenic mice in which the gene encoding the transcription factor, small heterodimer partner (SHP) has been disabled specifically in hepatocytes. Which of the following genes, involved in bile acid metabolism, would most likely exhibit unregulated expression in the livers of these mice?

A) bile salt export protein (BSEP)
B) farnesoid X receptor (FXR)
C) 3β-hydroxy-Δ⁵ C_-27-steroid oxidoreductase (HSD3B7)
D) 7α-hydroxylase (CYP7A1)
E) multidrug-resistance-associated protein 2 (MRP2)

Accepted Answer

SHP normally represses CYP7A1, a key enzyme in bile acid synthesis. Disabling SHP in hepatocytes would lead to increased expression of CYP7A1.

Question 6

Bile acids have been shown to control their own metabolism and transport via the enterohepatic circulation, regulate lipid metabolism, regulate glucose metabolism, and regulate overall energy expenditure. These effects of the bile acids are exerted via the binding to and activation of which of the following?

A) ChREBP
B) farnesoid X receptor (FXR)
C) 7α-hydroxylase (CYP7A1)
D) SREBP-1c
E) sterol 27-hydroxylase (CYP27A1)

Accepted Answer

Bile acids exert their effects by binding to and activating the farnesoid X receptor (FXR), which plays a crucial role in regulating bile acid metabolism, lipid metabolism, glucose metabolism, and energy expenditure.  Bile acids, in particular chenodeoxycholic acid (CDCA) and cholic acid (CA), can regulate the expression of genes involved in their synthesis, thereby creating a feedback loop. The elucidation of this regulatory pathway came about as a consequence of the isolation of a class of receptors called the farnesoid X receptors (FXRs), which were shown to bind to bile acids.

Question 7

A 6-month-old infant presents with progressive neurological dysfunction, cholestasis, bilateral cataracts, and chronic diarrhea. A diagnosis is made of a bile acid metabolism defect due to deficiency in the sterol 27-hydroxylase gene. Which of the following would be expected to be an additional finding in this infant?

A) decreased overall levels of chenodeoxycholic acid
B) decreased overall levels of cholic acid
C) elevated cholesterol in the gallbladder
D) elevated taurocholic acid in the biliary canaliculi
E) increased deoxycholic acid in the gallbladder

Accepted Answer

The alternative bile acid synthesis pathway involves hydroxylation of cholesterol at the 27 position by the mitochondrial enzyme sterol 27-hydroxylase (CYP27A1). This alternative pathway is referred to as the "acidic" pathway of bile acid synthesis. The product of this pathway is chenodeoxycholic acid, the same as for the classic pathway initiated by CYP7A1. However, the acidic pathway does not lead to the synthesis of cholic acid; so this bile acid and its metabolites would be reduced in individuals with a deficiency in CYP27A1. Although the acidic pathway accounts for no more than 6% of total bile acid production, it is an important as evidenced by the symptoms seen in infants harboring the defective gene.

Question 8

Which of the following modifications increases the working pH range and amphipathic nature of bile acids?&#10;A) conjugation to taurine or glycine&#10;B) dehydroxylation by intestinal bacteria&#10;C) esterification&#10;D) formation of sodium or potassium salts&#10;E) 7a-hydroxylation

Accepted Answer

Conjugation to taurine or glycine increases the working pH range and amphipathic nature of bile acids by making them more water-soluble and effective at emulsifying fats.  Bile acids are modified, prior to secretion from the liver into the bile canaliculi, by addition of the amino acid glycine or taurine. The addition of these amino groups increases amphipathic nature of bile acids making them more easily secretable as well as less cytotoxic.

Deck 27: Lipids: Bile Acid Metabolism