Biochemistry In complex diseases that are systemic throughout the body, there is
ID: 210775 • Letter: B
Question
Biochemistry
In complex diseases that are systemic throughout the body, there is often no way to model the disease process without the use of in vivo animal model systems. The study of lipid metabolism and atherosclerosis in the body relies on animal research to test hypotheses and develop new treatments to help improve human health.
You are working in a research team using several mouse strains that are gene knockouts for key proteins in cholesterol and apolipoprotein metabolism. Consider the following mouse strains, which have had genes turned off, referred to as “knockouts”:
- Apolipoprotein E knockout mice (Apoe/) that cannot make ApoE protein
- LDL receptor -/- mice( Ldlr/ ) that do not make LDL receptor.
- Apob100/100 mice expressing only ApoB-100 and not ApoB-48
- Apob48/48 mice expressing only ApoB-48 and not ApoB-100.
- Apob+/+ normal mice that express both forms of ApoB.
The two hypercholesterolemic mouse models, the apo E–deficient mouse (Apoe/) and the LDL receptor–deficient mouse (Ldlr/) have been used to study atherogenesis, or the development of fatty plaques at the start of atherosclerosis. On a normal mouse chow diet, Apoe/ mice have the highest cholesterol levels, with total cholesterol levels of ~400 mg/dL. Chow-fed Ldlr/ mice have mildly increased plasma cholesterol levels (175 to 225 mg/dL) from an accumulation of LDL and develop only minimal atherosclerotic lesions. Apo B-48 is the predominant apolipoprotein in the VLDL remnants of Apoe/ mice, whereas apo B-100 predominates in the LDL of Ldlr/ mice. The following table summarizes the characteristics observed in these two hypercholesterolemic mouse models.
These two knockout strains of mice have allowed scientists to investigate the genetic influence on atherosclerosis. Moreover, these mice can be fed controlled diets with different fat profiles and their health status can be closely monitored, which cannot be done in a human population. However, there are drawbacks to these models. In the case of the Ldlr-/- mice, there is a minimal development of the atherosclerotic plaques, even after 9-12 months, which is very late in a mouse life span. Conversely, Apoe-/- mice have incredibly high plasma cholesterol levels, far higher than normally observed in people, and it is mostly ApoB-48 associated cholesterol. Humans with high cholesterol normally have high ApoB-100, which is different from these mice. To understand the implications, mice expressing only ApoB-100 or ApoB-48 were also developed. These two strains have similar total and HDL cholesterol to Apob+/+ normal mice, but the Apob48/48 mice have significantly lower plasma TAG, while the Apob100/100 have significantly higher plasma TAG.
Based on your knowledge of Apolipoproteins in the different types of cholesterol, explain why you think there are these differences in lipoprotein and apolipoprotein composition between the four mouse strains of Apoe-/-, Ldlr-/-, Apob48/48, and Apob100/100 mice:
1. Why would LDLr knockouts have much more LDL/IDL particles compared to VLDL and HDL?
Apoe Mice 400 mg/dL, 5 times above controls Greatly increased Modestly increased Decreased 3 months streaks, 8 months plaques Many large plaques after 14 weeks Ldir Mice 200 mg/dL, 2-3 times higher than controls Modestly increased Greatly increased Modestly increased Phenotype Hypercholesterolemia (cholesterol in the blood) VLDL IDL/LDLe HDL Spontaneous fatty plaques Medium plaques after 12 weeks on high cholesterol diet High fat diet induced plaquesExplanation / Answer
Ans .
There are differences in lipoprotein and apolipoprotein composition between the four mouse strains of Apoe-/-, Ldlr-/-, Apob48/48, and Apob100/100 mice, because
- apolipoprotein E-deficient (Apoe/) mice display poor lipoprotein clearance with subsequent accumulation of cholesterol ester-enriched particles in the blood.
- mice lacking LDL receptors (LDLR-/- ) display 2-3 times higher cholesterol in the blood due to increase in intermediate density lipoproteins (IDL) and LDL without a significant change in HDL.
- the Apob48/48 mice have significantly lower plasma TAG, while the Apob100/100 have significantly higher plasma TAG because lipolysis may be less efficient with apoB-100-containing lipoproteins than with apoB-48-containing lipoproteins, either because of intrinsic differences in the apoB molecules or because apoB-48- and apoB-100-containing lipoproteins differ in their content of other apolipoproteins that could affect the extent and speed of lipolysis.
1. LDLr knockouts have much more LDL/IDL particles compared to VLDL and HDL because LDLr (low-density lipoprotein receptor) binds to low-density lipoproteins (LDLs) and intermediate-density lipoprotein (IDLs).
LDLr sit on the outer surface of many types of cells, where they pick up LDLs/IDLs circulating in the bloodstream and transport them into the cell. Once inside the cell, the LDLs/IDLs are broken down to release cholesterol. The cholesterol is then used by the cell, stored, or removed from the body. After low-density lipoprotein receptors drop off their cargo, they are recycled back to the cell surface to pick up more LDLs/IDLs. that's why LDLr knockouts have much more LDL/IDL particles compared to VLDL and HDL as LDLr is not present these knockout mice.
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