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CASE FILES: BIOCHEMISTRY
A nsw ers
[31.1]
D. Conjugation of bile acids to these two amino acids through amide
linkages is important for maintaining the detergent properties of bile
salts over the wide pH range of the intestinal tract. Conjugation
decreases the pKa of the bile salts assuring ionization and solubility
in the intestines.
[31.2]
D. Any of the situations in answers A to C could directly alter cho-
lesterol and bile acid homeostasis. Many of the bile acid transporters
are regulated by nuclear receptors. Therefore, a nuclear receptor lig-
and such as CT2033 could change the expression levels of the trans-
porters, which could then result in problems with secretion of bile
acids and probable accumulation of cholesterol. If the new drug were
to directly bind and inhibit the transporter, the same result would
occur. Since corticosteroids are derivatives of cholesterol, it could be
reasonable for CT2033 to fit in the same
CYP7A1
binding pocket and
compete with cholesterol. This could cause accumulation of choles-
terol because
CYP7A1
is needed to convert cholesterol into bile salts.
The drug could act to effectively lower active
CYP7A1
levels.
However, answer D is least likely to affect cholesterol and bile acids
since pancreatic lipases are involved in the breakdown of fat. Bile
acids simply emulsify fats and allow pancreatic lipases to degrade the
fat. Therefore, inhibiting pancreatic lipases should not have much of
an effect on cholesterol and bile acid homeostasis.
[31.3]
C. A loss in function of
CYP7A1
prevents the catabolism of choles-
terol to bile salts. Elevated levels of LDL cholesterol, signs of pre-
mature cholesterol gallstone disease, and substantially elevated
triglycerides are all complications that can result from blocking the
enzyme that breaks down cholesterol. Therefore, high levels of cho-
lesterol accumulate in the bile and, with decreased production of bile
salts to help dissolution of cholesterol, the formation of cholesterol
gallstones. Statin therapy is not as effective because it inhibits the
enzyme that controls the rate of cholesterol synthesis but does noth-
ing with respect to the degradation of cholesterol. The increase in
blood triglyceride levels when
CYP7A1
is deficient is not well under-
stood, but triglyceride levels appear to have a reciprocal relationship
to bile acid synthesis. Finally, this appears to be a genetic disorder
since other siblings showed the same phenotype, which would point
to a possible mutated gene and likely prevent function of
CYP7A1.
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