Feodor Lynen (1975) - The Regulation of Cholesterol Synthesis and its Pathophysiologic Meaning (German presentation)

Feodor Lynen (1975)

The Regulation of Cholesterol Synthesis and its Pathophysiologic Meaning (German presentation)

Feodor Lynen (1975)

The Regulation of Cholesterol Synthesis and its Pathophysiologic Meaning (German presentation)

Comment

The present lecture is the last of three given by Feodor Lynen in Lindau from 1966 to 1975. Like his 1972 lecture, it is concerned with cholesterol, a steroid which is, at the same time, an essential constituent of our tissues and a major health threat due to its tendency to form solid deposits in arteries causing blockages and arteriosclerosis (background information on cholesterol can be found in the comment on Lynen’s 1972 lecture).

For the major part of the present lecture, Lynen is concerned with discussing new data on the regulation of cholesterol synthesis in our bodies. The rate of this synthesis is adjusted according to the cholesterol intake via food. If more cholesterol is consumed, less is synthesized and vice versa. Synthesis proceeds via the so-called mevalonate pathway, a sequence of enzymatically controlled, biochemical reactions. The mevalonate pathway yields isopentenyl pyrophosphate, the compound that Lynen refers to as activated isoprene (“aktiviertes Isopren”). Isopentenyl pyrophosphate is the core building block required for cholesterol synthesis. Regulating the rate of its production in the mevalonate pathway is one of our body’s means of controlling cholesterol levels.

Today (2013) we know, that a complex range of mechanisms and feedback loops are involved in the regulation of cholesterol biosynthesis. Not all of them were elucidated at the time of Lynen’s talk. However, it had already become obvious that they all have one thing in common: they work by affecting a single enzyme involved mevalonate pathway. This enzyme, called HMG-CoA reductase, converts HMG-Coenzyme A to mevalonate, which is then further reacted to yield activated isoprene. The regulation of cholesterol synthesis thus takes place at a relatively early stage: activated isoprene contains only five of the 27 carbon atoms present in cholesterol.

Interestingly, cholesterol itself has a major impact on cholesterol biosynthesis: it can deactivate the HMG-CoA reductase enzyme and trigger its degradation in the proteasome. Cholesterol furthermore affects the expression of genes coding for the HMG-CoA reductase enzyme. Hence, less HMG-CoA reductase is made if cholesterol levels are high. Both mechanisms reduce the rate of cholesterol synthesis and help to avoid excessive cholesterol accumulation. A further regulation mechanism involves the phosphorylation (covalent modification) of the HMG-CoA reductase enzyme by other enzymes, thus reducing its activity.

Unfortunately, Lynen himself could not witness the elucidation of the comprehensive picture of cholesterol regulation we have today. He died from the consequences of an aneurism operation in August 1979 [1].

David Siegel

[1] Angewandte Chemie International Edition 2011, 50, page 11580.

Rate this content

 (<5 ratings)

Cite


Specify width: px

Share

Rate this content

 (<5 ratings)

Cite


Specify width: px

Share


Related Content