Question

Biochemistry

1. what is the biochemical cause for familial hypercholestemia?

2. What enzyme is targeted by the current cholesterol lowering drugs, the stains?

3. Under roles of lipoprotein and their interactions with the intestine, adipocytes liver and peripheral tissue.

4. The largest drugs to be approved as cholesterol lowering drugs are bind irreversibly to PSSCK9 protein. Find out what the role of PCSK9 is and why inhibitors of them would lower serum cholesterol level?

Answer 1

1) Familial hypercholesterolemia (FH) is a dominantly-inherited disorder attributable to a defect in the low-density lipoprotein (LDL) receptor gene. Five mutations at this locus have been identified in French-Canadians. In children, it may be difficult to clinically distinguish FH from other forms of polygenic or monogenic hyperlipidemia. Therefore, our objectives were to define the molecular basis of our subjects' hypercholesterolemia, to characterize their biochemical phenotype in relation to the underlying molecular defect, and to assess their response to chronic dietary therapy.

2) Statins inhibit an enzyme called HMG-CoA reductase, which controls cholesterol production in the liver. The medicines actually act to replace the HMG-CoA that exists in the liver, thereby slowing down the cholesterol production process. Additional enzymes in the liver cell sense that cholesterol production has decreased and respond by creating a protein that leads to an increase in the production of LDL (low density lipoprotein, or "bad" cholesterol) receptors. These receptors relocate to the liver cell membranes and bind to passing LDL and VLDL (very low density lipoprotein). The LDL and VLDL then enter the liver and are digested. Statins (or HMG-CoA reductase inhibitors) are a class of cholesterol lowering drugs that inhibit the enzyme HMG-CoA reductase which plays a central role in the production of cholesterol. High cholesterol levels have been associated with cardiovascular disease (CVD). Statins have been found to prevent cardiovascular disease and mortality in those who are at high risk.

3)The role of lipoprotein particles is to transport triacylglycerols (a.k.a. triglycerides) and cholesterol in the blood between all the tissues of the body. The most common being the liver and the adipocytes of adipose tissue. Particles are synthesized in the small intestine and the liver, but interestingly not in the adipocytes.

4)During the past few years, the proprotein convertase subtilisin kexin 9 (PCSK9) field has been red hot, fueled by the realization that PCSK9 is a key player in plasma cholesterol metabolism and by a hope, shared by scientists in academia and industry alike, that PCSK9 is a target for treating hypercholesterolemia. PCSK9 regulates the levels of the LDL receptor (1–3), which is a plasma membrane glycoprotein that removes cholesterol-rich LDL particles from the plasma (4, 5). Gain-of-function mutations in PCSK9 reduce LDL receptor levels in the liver, resulting in high levels of LDL cholesterol in the plasma and increased susceptibility to coronary heart disease (6). Loss-of-function mutations lead to higher levels of the LDL receptor, lower LDL cholesterol levels, and protection from coronary heart disease (7–11). The loss of PCSK9 appears to have no adverse consequences (11). Thus, interest in PCSK9 as a cholesterol-lowering target has been high, and an army of investigators is now working to elucidate PCSK9 molcular interactions and physiology. In this issue of the Journal of Lipid Research (JLR), two leading research groups describe their recent efforts.