Cerebrotendinous xanthomatosis, sitosterolemia, Smith-Lemli-Opitz syndrome and the seminal contributions of Gerald Salen, MD (1935-2020).

Cerebrotendinous xanthomatosis (CTX), sitosterolemia, and Smith-Lemli Opitz syndrome (SLOS) are rare inborn errors of metabolism. The diagnoses of CTX and sitosterolemia are often delayed for many years because of lack of physician awareness, often resulting in significant and unnecessary progression of disease. CTX may present with chronic diarrhea, juvenile onset cataracts, strikingly large xanthomas, and neurologic disease in the setting of a normal serum cholesterol, but markedly elevated serum or plasma cholestanol levels. These patients have a defect in producing the bile acid chenodoxycholate, and oral chenodeoxycholate therapy is essential for these patients in order to prevent neurologic complications. Sitosterolemia can present with xanthomas, anemia, thrombocytopenia, splenomegaly, very premature heart disease, and serum cholesterol levels that may be normal or elevated, along with marked elevations of plasma ß-sitosterol. These patients have a defect causing overabsorption of ß-sitosterol, and the treatment of choice is oral ezetimibe. SLOS presents with growth delay, intellectual disability, multiple structural anomalies, and low serum cholesterol levels, and the defect is reduced cholesterol production. Treatment consists of dietary cholesterol supplementation and oral bile acid therapy which raises serum cholesterol levels and may improve symptoms. The metabolic and genetic defects in these disorders have been defined. There is no one in our field that has contributed more to the diagnosis and treatment of these disorders than Gerald Salen, MD, who died in late 2020 at 85 years of age. He will be greatly missed by his family, friends, and colleagues from around the world.

Sitosterolemia: Twenty Years of Discovery of the Function of ABCG5ABCG8.

Sitosterolemia is a lipid disorder characterized by the accumulation of dietary xenosterols in plasma and tissues caused by mutations in either ABCG5 or ABCG8. ABCG5 ABCG8 encodes a pair of ABC half transporters that form a heterodimer (G5G8), which then traffics to the surface of hepatocytes and enterocytes and promotes the secretion of cholesterol and xenosterols into the bile and the intestinal lumen. We review the literature from the initial description of the disease, the discovery of its genetic basis, current therapy, and what has been learned from animal, cellular, and molecular investigations of the transporter in the twenty years since its discovery. The genomic era has revealed that there are far more carriers of loss of function mutations and likely pathogenic variants of ABCG5 ABCG8 than previously thought. The impact of these variants on G5G8 structure and activity are largely unknown. We propose a classification system for ABCG5 ABCG8 mutants based on previously published systems for diseases caused by defects in ABC transporters. This system establishes a framework for the comprehensive analysis of disease-associated variants and their impact on G5G8 structure-function.

Lipoprotein-X fifty years after its original discovery.

AIMS: To review the formation, catabolism, and the possible atherogenic properties of Lp-X. DATA SYNTHESIS: The conversion of cholesterol to bile acids is regulated by several mechanisms including cholesterol 7 alpha hydroxylase, fibroblast growth factor 19, and farnesoid X receptors. During cholestasis these mechanisms are altered and there is an accumulation of bile acids and cholesterol in plasma. The hypercholesterolemia observed in cholestasis is due to the presence of an anomalous lipoprotein called lipoprotein-X (Lp-X). Lp-X is a lipoprotein rich in phospholipid and free cholesterol present in plasma of patients with cholestasis and, with some variations, in patients with lecithin-cholesterol-acyl-transferase deficiency (LCAT), and after lipid infusion. Lp-X is formed from a bile lipoprotein moving to the blood vessels where it incorporates small quantities of triglycerides, apo-C and esterified cholesterol and becomes a "mature" Lp-X. The activity of the phosphatidilcholine canalicular transporter Mdr2 P-glycoprotein (homologous to the human ABCB4) is essential for LpX appearance, since its suppression abolishes Lp-X formation. However, the concentration of Lp-X in plasma is determined also by the degree of the cholestasis, the residual liver function, and the LCAT deficiency. The Lp-X catabolism seems to be mediated by the reticuloendothelial system and possibly the kidney. CONCLUSIONS: Lp-X might be considered a defense mechanism against the toxic effect of free cholesterol in cholestasis. The frequency of cardiovascular events in patients affected by primary biliary cholangitis, in whom the Lp-X is present in high concentration, are not increased. Further studies could now clarify the remaining open questions on the role of Lp-X in the dyslipidemia of cholestasis.

The Success Story of LDL Cholesterol Lowering.

We can look back at >100 years of cholesterol research that has brought medicine to a stage where people at risk of severe or fatal coronary heart disease have a much better prognosis than before. This progress has not come about without resistance. Perhaps one of the most debated topics in medicine, the cholesterol controversy, could only be brought to rest through the development of new clinical research methods that were capable of taking advantage of the amazing achievements in basic and pharmacological science after the second World War. It was only after understanding the biochemistry and physiology of cholesterol synthesis, transport and clearance from the blood that medicine could take advantage of drugs and diets to reduce the risk of atherosclerotic diseases. This review points to the highlights of the history of low-density lipoprotein-cholesterol lowering, with the discovery of the low-density lipoprotein receptor and its physiology and not only the development of statins as the stellar moments but also the development of clinical trial methodology as an effective tool to provide scientifically convincing evidence.

The history of Autosomal Recessive Hypercholesterolemia (ARH). From clinical observations to gene identification.

The most frequent form of monogenic hypercholesterolemia, also known as Familial Hypercholesterolemia (FH), is characterized by plasma accumulation of cholesterol transported in Low Density Lipoproteins (LDLs). FH has a co-dominant transmission with a gene-dosage effect. FH heterozygotes have levels of plasma LDL-cholesterol (LDL-C) twice normal and present xanthomas and coronary heart disease (CHD) in adulthood. In rare FH homozygotes plasma LDL-C level is four times normal, while xanthomas and CHD are present from infancy. Most FH patients are carriers of mutations of the LDL receptor (LDLR); a minority of them carry either mutations in the Apolipoprotein B (ApoB), the protein constituent of LDLs which is the ligand for LDLR, or gain of function mutations of PCSK9, the protein responsible for the intracellular degradation of the LDLR. From 1970 to the mid 90s some publications described children with the clinical features of homozygous FH, who were born from normocholesterolemic parents, strongly suggesting a recessive transmission of FH. In these patients the involvement of LDLR and APOB genes was excluded. Interestingly, several patients were identified in the island of Sardinia (Italy), whose population has a peculiar genetic background due to geographical isolation. In this review, starting from the early descriptions of patients with putative recessive hypercholesterolemia, we highlight the milestones that led to the identification of a novel gene involved in LDL metabolism and the characterization of its encoded protein. The latter turned out to be an adaptor protein required for the LDLR-mediated endocytosis of LDLs in hepatocytes. The loss of function of this protein is the cause of Autosomal Recessive Hypercholesterolemia (ARH).

Neem (Azadirachta indica): prehistory to contemporary medicinal uses to humankind.

The divine tree neem (Azadirachta indica) is mainly cultivated in the Indian subcontinent. Neem has been used extensively by humankind to treat various ailments before the availability of written records which recorded the beginning of history. The world health organization estimates that 80% of the population living in the developing countries relies exclusively on traditional medicine for their primary health care. More than half of the world's population still relies entirely on plants for medicines, and plants supply the active ingredients of most traditional medical products. The review shows the neem has been used by humankind to treat various ailments from prehistory to contemporary.

History of the cholesterol controversy in Britain.

The lipid hypothesis, the concept that cholesterol plays a causal role in atherosclerosis and cardiovascular disease, has been the subject of a controversy which started in the 1950s, peaked in the 1970s and 80s and then subsided in the 1990s. It was finally resolved by the positive outcome of the Scandinavian Simvastatin Survival Study, the first of 14 prevention trials using statins which showed that lowering cholesterol reduced both cardiovascular events and total mortality. This commentary focuses primarily on the events and people involved in the cholesterol controversy in Britain. The foremost critics of the lipid hypothesis are now deceased but unfortunately for many of the patients with hypercholesterolaemia and coronary heart disease it took the best part of 50 years to disprove the sceptics. This brief account relates why it took so long.

Sobre el descubrimiento de los fármacos hipolipemiantes / About the discovery of hypolipidemic drugs

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Special issue dedicated in memory of Dr. Edward H. Ahrens, Jr.

This special issue of the "Cardiovascular Drug Reviews" is dedicated in memory of Dr. Edward H. Ahrens, Jr., who died on Dec. 9th, 2000 at the Princeton Medical Center in New Jersey at the age of 85. Dr. Ahrens was the Director of the Lipid Metabolism Laboratory at the Rockefeller University. Dr. Alexander Scriabine conceived the idea for the issue at the special memorial symposium held at the Rockefeller University on Feb. 05, 2002 under the auspices of The New York Lipid and Vascular Biology Research Club. Dr. Ahrens was the first president of the club. He started this club with Drs. Howard Eder and DeWitt Goodman. Dr. Eder thought that it would be a fitting attribute to honor one of the founding fathers of the club by hosting a memorial symposium. I, as the President of the club for that academic year, had no hesitation in accepting the proposal. This year will be the 40th anniversary of the club and its continued success provides a glimpse of the fine legacy left behind by Dr. Ahrens. Dr. Ahrens also played a pivotal role in the establishment of the Journal of Lipid Research. This is the 43rd year of the journal and in this commemorative issue we are reproducing a review he wrote for the 25th anniversary of the journal. I was never personally acquainted with Dr. Ahrens. However, I am honored that I got this opportunity to pay tribute to a great scientist whose work has contributed immensely to the progress of lipid research. He was a person who touched many lives and still continues to do so. My involvement in the remembrance of Dr. Ahrens shows that science not only impacts your contemporaries but also generations that follow you. Scientific research is a journey where you can leave your trails behind and be remembered for your work long after your departure from this world. Dr. Ahrens contributed immensely to the understanding of cholesterol metabolism. In the early stages of his career he showed that phospholipids solubilize fat in the blood. Now we know that a monolayer of phospholipids surrounds the neutral lipid core of cholesterol esters and triglycerides in lipoproteins. This monolayer contains proteins, called apolipoproteins, which play a major role in lipoprotein catabolism. Lipoproteins are the major vehicles that transport triglycerides and cholesterol in the plasma. He also described a new form of primary biliary cirrhosis characterized by the presence of xanthomas and hyperlipidemia with normal translucent plasma. Subsequently, his group at the Rockefeller Institute developed methods for the separation of lipids using silicic acid columns, isolated highly unsaturated long chain fish oil fatty acids using gas-liquid chromatography, standardized techniques to study sterol metabolism, and introduced the concept of using beta-sitosterolemia as an internal marker for cholesterol balance studies. These studies revealed that individuals show a reproducible response to a given regimen when studied over time. In contrast, different individuals may respond differently to the same regimen. Throughout his career, Dr. Ahrens championed metabolic studies in humans and has passionately argued for the continuation of such investigations. Dr. Ahrens also left behind trails of "graduates." Several of them are currently prominent scientists in their own fields. In this issue, Drs. Davignon and Samuel share their feelings for him in the form of "Remembrance" and "Curriculum Vitae." Dr. Salen has submitted a preview of his research progress towards the understanding of sitosterolemia. Dr. Hudgins and associates have acknowledged the efforts of Dr. Ahrens in binding LDL apheresis technique to the United States of America and have previewed the use of this procedure in the treatment of hypercholesterolemic patients. The contributions of these and other graduates will keep his legacy alive for a long time to come. We are truly grateful for this opportunity to pay homage to such a distinguished scientist.