When was hdl discovered

In the lysosome, both the apoprotein and lipids of LDL are degraded to monomers and released into the cytoplasm. The free cholesterol released has the following four effects: 1 incorporation into membranes; 2 inhibition of the synthesis of new LDL receptors; 3 inhibition of cholesterol synthesis by reducing the synthesis of HMG CoA reductase; and 4 promotion of the activity of acyl CoA:cholesterol acyltransferase ACAT , which synthesizes cholesterol esters.

These regulatory events are mediated by a sterol regulatory element binding protein, which monitors the free cholesterol concentration in the cell and adjusts the expression of the cholesterol regulatory genes Wang et al. The turnover of LDL receptors occurs partially as a result of recycling receptors that have undergone endocytosis and partially by new synthesis.

Sequential steps in the LDL-pathway for mammalian cells. The LDL receptor accomplishes the endocytosis of LDL by producing a vacuole, which merges with a lysosome which, in turn, digests the protein and lipids of LDL to produce monomers that diffuse into the cytoplasm.

The dark lines of LDL indicate protein; the diagonal lines indicate lipid. Modified from Brown and Goldstein Knowledge of the importance of lipoprotein receptors, which feature protein-protein interactions in the clearance of circulating lipoproteins, has modernized views of fat transport; the pathways are shown in Figure 4.

Within the liver, the chylomicron remnant is decomposed to its amino acids and component lipids. Cholesterol released from lysosomes in hepatocytes can be excreted into bile, converted into bile acids, incorporated into VLDL for secretion into the blood via the Golgi apparatus or esterified with long-chain fatty acids and stored in the hepatocyte.

Receptor-mediated pathways of lipoprotein metabolism. LDL, which contains only apolipoprotein B, is the final product of the pathway; most of it is returned to the liver. The apopeptides contained in each lipoprotein are indicated. VLDL, the main secretory lipoprotein of the liver, contains cholesterol, phospholipid, triglyceride, newly synthesized B and small amounts of E and C apopeptides. The average turnover time for chylomicron triglycerides in the blood is 7 min, whereas that for VLDL triglycerides is about 20 min.

LDL is the most prominent lipoprotein in human plasma, has a turnover time of about 3 d and is cleared principally by LDL-receptors. A precursor of HDL containing A1-, A2- and A3-apopeptides, phospholipids and free cholesterol is also synthesized in the liver and secreted into the blood.

Apo A1, a co-factor for lecithin:cholesterol acyl transferase, stimulates this enzyme to transfer fatty acids from lecithin to cholesterol to form cholesterol ester, which enables HDL-3 to assume its spherical shape with a hydrophobic center and a more polar exterior. HDL accomplishes reverse cholesterol transport from extrahepatic tissues to the liver. Genetic errors in the synthesis or metabolism of plasma lipoproteins or their regulatory enzymes account for the hyper- and dyslipoproteinemias observed in clinical studies, which are beyond the scope of this review Breslow Three disease states that are known to be promoted by changes in plasma lipoprotein concentrations in individuals are as follows: 1 atherosclerosis; 2 xanthomatosis; and 3 Alzheimer's disease.

Alterations in apo E structure relate to all three of these conditions. The atheromatous plaque was first described by Virchow as the fundamental lesion of atherosclerosis. It is characterized by smooth muscle proliferation, accumulation of connective tissue fibers and matrix, and lipid accumulation.

Usually there is a fibrous cap made up of collagen plus smooth muscle cells, and below that, a disorganized mass of lipids, cholesterol clefts, cell debris, fibrin and other plasma proteins. Calcification, ulceration and hemorrhage into the plaque may occur. Thannhauser and Magendantz were among the first to associate both atherosclerosis and xanthoma with high serum cholesterol levels. Cholesterol per se is not the agent because LDL, which contains cholesterol, is pro-atherogenic whereas HDL, which also contains cholesterol, is anti-atherogenic.

A xanthoma is a discrete, raised yellow lesion of the skin Addison and Gull, Xanthomas are benign tumors characterized by collections of foamy histocytes. They occur in all races and both sexes in association with familial or acquired disorders leading to hyperlipidemia. Apo E mRNA is abundant in the brain where apo E is synthesized and secreted principally by astrocytes.

Apo E—containing lipoproteins are found in the cerebral spinal fluid and appear to play a major role in lipid transport in the central nervous system. Apo E plus a source of cholesterol promotes marked neuritic extension of the dorsal root ganglion cells in culture, and apo E levels dramatically increase after peripheral nerve injury.

Apo E-4, a mutant form of apo E-3, has been implicated in the pathogenesis of Alzheimer's disease. Apo E-3 also inhibits phosphorylation of tau, which tends to prevent the formation of neurofibrillar tangles, whereas apo E-4 does not affect the phosphorylation of tau Mahley et al.

A century ago, knowledge about the relations of plasma proteins to lipids was fragmentary. Nerking observed that the digestion of plasma protein with pepsin liberated a mixture of free lipids, but the discovery of the lipoproteins responsible was delayed for many years. From then on, many laboratories identified other lipoproteins, measured their concentration in plasma and studied their turnover in metabolism. On the basis of these studies, a view of fat transport involving triglyceride and FFA movements was formulated in the s.

Not until , however, when Brown and Goldstein discovered the LDL-receptor, was it realized that fat transport depended upon a series of receptor-mediated events.

Most of the clinical hyperlipidemias have been found to be the result of genetic changes in lipoproteins, their receptors or the enzymes that mold lipoproteins in plasma. Finally, one isoform of apopeptide E has proven to play a role in Alzheimer's disease. Addison , T. Guy's Hosp. VII: — Berg K. A new serum type system in man: the Lp-system. Acta Pathol. Google Scholar. Blix G. Tiselius A.

Svensson M. Lipids and polysaccharides in electrophoretically separated blood serum proteins. Boudet M. Nouvelle recherches sur la composition du serum du sang humain. Breslow J. Apolipoprotein genetic variation and human disease. Brown M. Goldstein J. Familial hypercholesterolemia: defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxymethylglutaryl coenzyme A reductase activity.

Receptor-mediated endocytosis: insight from the lipoprotein receptor system. Koch's postulates for cholesterol. Cell 71 Chevreul M. Chick H. The apparent formation of euglobulin from pseudoglobulin and a suggestion as to the relationship between these two proteins in serum. Cohn E. Strong L. Hughes W. Mulford D. Ashworth J. Melin M. Taylor H. Preparation and properties of serum and plasma proteins. A system for the separation into fractions of the proteins and lipoprotein components of biological tissues and fluids.

Dam , H. In: Chemistry, Biochemistry and Pathology R. Cook ed. Google Preview. Dole V. A relation between non-esterified fatty acids in plasma and the metabolism of glucose. Subsequently, it was discovered that the free fatty acids FFA in plasma were bound to albumin and varied with feeding and fasting.

From further studies, it was concluded that lipoprotein-bound triglycerides were delivered to adipose cells for uptake after meals; during fasting, the fat cells secreted FFA, which provided fuel for many tissues. The protein components of the lipoproteins apopeptides were characterized in the period from to and the LDL-receptor was identified in However, now back to another very important discovery in lipidology - the LDL receptor by Joseph Goldstein b.

They met during their internships in the late s and were intrigued by FH [17]. Their lifelong partnership also extended to the bridge table, and both received the Nobel prize in [17].

With permission from Eur Heart J. The resulting guidelines became the gold standard on how and who to treat [22]. In , the first ApoE knock-out mouse model was introduced [19]. In , mutations were found in proprotein convertase subtilisin kexin-9 PCSK9 as a cause for autosomal dominant hypercholesterolaemia [23]. Before reaching the lifechanging era of cholesterol-lowering drugs in the s, other options were tested. Nicotinic acid Niacin was first synthesised by Albert Ladenburg in [8].

Rudolf Altschul finally discovered cholesterol lowering properties in [8]. This lasted until when Anna Lorenzen described the mechanism - via the nicotinic acid receptor [8]. The Dow Chemical Company developed cholestyramine as a water softener. It became available in In , Sami Hashim and Theodore Van Itallie reported a clinical study showing cholesterol lowering, which caused great excitement in the field of cardiology [8].

As its smell and taste were awful, Robert Fuson added orange flavour to cholestyramine in for Mead Johnson Laboratories [8]. The rights for cholestyramine were with Merck and, after selling it to Bristol Myers Squibb, it was marketed as Questran [8].

Upjohn, in the meantime, had developed a similar product, colestipol Colestid [8]. They discovered clofibrate not a plant sterol and marketed this under the name Atromid-S in [8]. Gemfibrozil was patented in and came into medical use in under the name Lopid. In the s, by serendipity, it was found that, whilst removing a part of the thyroid as anti-anginal therapy! Hence, it was deduced that supplying dextrothyroxine should lower cholesterol [8].

In , several cardiologists reported seeing good results in lowering cholesterol by using equine oestrogens Premarin [8]. During enrolment, dextrothyroxine as well as oestrogens were stopped. Just before FDA evaluation, it appeared that serious side effects in animals cataract, hair loss were not reported; in , a lawsuit was the end of this scandal [12].

It was more than a decade before new developments were reported. In , Akira Endo b. At the same time, Beecham Pharmaceuticals also discovered this from Penicillium brevicompactum [7].

The development of compactin as a drug by Sankyo was, however, stopped in , due to claims that it caused lymphomas in dogs in fact these dogs received times the dose patients would have received [7].

The search went on for other statins. Merck in agreement with Sankyo, obtained samples of compactin in In , they isolated mevinolin from Aspergillus terreus [7]. Endo, who had left Sankyo, also discovered monacolin K from Monascus ruber in The substances appeared to be the same later renamed lovastatin.

In , after five months of development, lovastatin clinical trials were stopped by Merck due to rumours that this also caused cancer in dogs [7].

As clinicians kept showing impressive results of lowering cholesterol using statins, Merck was persuaded to restart large clinical lovastatin trials in This led to FDA approval of lovastatin Mevacor as the first commercial statin at the end of [7, 8]. Simvastatin followed, and Sankyo developed and launched pravastatin in By , two semi-synthetic statins, simvastatin Zocor, Merck, and pravastatin Pravachol, BMS, , and four synthetic statins, fluvastatin Lescol, Sandoz, , atorvastatin Lipitor, Parke-Davis, , rosuvastatin Crestor, AstraZeneca, and pitavastatin, were introduced to the market [7, 8].

However, it had to be taken off the market in , because of substantial side effects: the prevalence of rhabdomyolyse was times higher, and deaths were reported [8]. In , ezetimibe was introduced Schering-Plough , an intestinal cholesterol absorption inhibitor. Nabil Seidah b. The first results of the Coronary Primary Prevention Trial which started in were published in [22]. The intervention group took high doses of cholestyramine, and both groups placebo and intervention followed a mild diet.

The Scandinavian Simvastatin Survival Study 4S , published in , showed for the first time a significant decrease in all-cause mortality [12]. This finding led to new guidelines which advised lowering LDL levels even further.

The discussion was also influenced by the fact that Bill Clinton experienced his heart attack after stopping simvastatin [8]. At this moment, developments and discoveries go faster than ever before when compared to their historical counterparts.

In , alternatives for anti-PCSK-9 antibodies were being tested, e. Every cloud has a silver lining. The scientific work on cholesterol and lipids led to at least 11 Nobel prizes. Although the mortality benefits are much smaller than assumed, cholesterol-lowering therapy is widely accepted and is beyond any doubt a preventive means in vascular diseases.

Developments in medication advance much faster nowadays than history could ever have predicted, and they quickly result in new guidelines. For almost a century, evidence has been overwhelming that lipids and diet are related and have a negative impact on CVD. It is also clear that lipids, and especially LDL, play a crucial role in atherosclerosis. Importantly, we should never forget that patients are individuals and LDL is not the holy grail. As early as , diet, mental stress, obesity, a sedentary lifestyle and smoking were mentioned as risk factors besides lipids.

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To get the best experience using our website we recommend that you upgrade to a newer version. Learn more. Show navigation Hide navigation. Sub menu. History in medicine: the story of cholesterol, lipids and cardiology Vol. Petra M.

Topic s : Lipids. Introduction Checking lipid values and prescribing lipid-lowering drugs is core business for cardiologists. History The word cholesterol consists of chole bile and stereos solid , followed by the chemical suffix -ol for alcohol. Figure 1. Chemical structure of cholesterol. Lipoproteins In , Michel Macheboeuf suggested that circulating lipids exist in complexes with proteins: this was the discovery of lipoproteins [10, 13].