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个人简介
Dan’s scientific achievements included pioneering studies in fatty acid metabolism and hormone-sensitive lipase, elucidating the metabolic basis for Refsum’s disease, and development of innovative methods to measure lipoprotein synthesis and the sites of lipoprotein degradation in vivo.
Although these accomplishments were the basis for his election to the National Academy of Sciences in 1982, Dan was just then embarking on what would become his most important scientific contribution: the discovery of the role of low-density lipoprotein (LDL) oxidation in the pathogenesis of atherosclerosis.
known to be sufficient to cause atherosclerosis in humans and animal models, but the mechanisms were unclear. Michael Brown and Joseph Goldstein had by the late 1970s shown that uptake of LDL by cells was primarily mediated by LDL receptors that were down-regulated when cellular cholesterol needs were satisfied. However, massive levels of LDL cholesterol accumulated within macrophages in atherosclerotic lesions. Incubation of macrophages with even very high levels of native LDL in vitro failed to recapitulate this phenotype because of downregulation of LDL receptors. So how macrophages became foam cells in the artery wall was a mystery. Brown and Goldstein reasoned that macrophages function to scavenge damaged molecules and that somehow LDL must be modified, leading to unregulated uptake by an alternative pathway. The researchers showed that acetylation of lysine residues of the protein component of LDL allowed uptake through a constitutive “scavenger receptor” pathway of macrophages, but because of the artificial nature of the LDL modification, the relevance of this pathway to atherosclerosis was unclear.
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PIONEERS OF MEDICINE WITHOUT A NOBEL PRIZE (2014)
mag(2013)
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Journal of Lipid Researchno. 7 (2011): 1305-1306
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