Discoveries concerning the regulation of cholesterol metabolism
Michael S Brown and Joseph L Goldstein were awarded in 1985 the Nobel Prize of Physiology and Medicine for their work on the regulation of the cholesterol mechanism.
They began their work on HMG CoA reductase, a protein responsible for synthesising cholesterol in the body, following earlier studies in rats that showed the protein’s activity was reduced when the rats ingested cholesterol. They soon found that this was due to regulation in fibroblast cells (cells that form the connective tissue) and this also applied to cultured human fibroblast cells.
Of the two main cholesterol-carrying lipoproteins found in humans, LDL and HDL, only LDL was effective at triggering this regulation. This suggested that there must be a specific receptor for detecting LDL that controls this process. In cells from patients with familial hypercholesterolemia the HMG CoA reductase activity were up to 100 times higher than normal and did not respond to changes in concentrations of LDL.
Further work using tissues from cows and animals allowed Goldstein and Brown to develop assays for studying the behaviour of the receptor responsible. This work, in combination with others’ work using animals to study the uptake of radiolabelled LDL into various tissues, helped to understand the behaviour of LDL in the body. In 1982, Goldstein and Brown’s laboratory purified the hypothesized LDL receptor from bovine adrenal glands before isolating the human gene three years later.
A strain of mutant rabbits with a similar mutation in the LDL receptor gene as humans with familial hypercholesterolemia was discovered by a veterinarian in Japan in the 1970s. These rabbits had extremely high LDL levels and developed atherosclerosis in early life. By virtue of their condition being so similar to that seen in humans, they were used to further understand the disease and determine why these patients also appear to produce more LDL, as well as being unable to detect it.