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BACKGROUND: Hyperglycemia during hospital stay is associated with adverse outcomes. AIM: To characterize the frequency of hyperglycemia in a tertiary hospital and to correlate it with length of hospital stay (LOS). MATERIAL AND METHODS: Review of medical records of hospitalized patients. Demographic data and laboratory data, previous diabetes mellitus (DM) history, current main diagnosis, unit of hospitalization and the two highest capillary blood glucose values from the analyzed period were recorded for each patient. LOS was obtained from electronic clinical records. RESULTS: 210 subjects, aged 60 ± 19 years (104 women) were included. 113 patients (54%) developed hyperglycemia ≥ 140 mg/L. Thirty one percent of these had a previous history of diabetes and 29% had stress hyperglycemia (SHG). Patients with a history of DM had a higher average blood glucose than those with SHG (238.9 and 178.2 mg/dL, respectively, p < 0.01) and a greater percentage of cases with a blood glucose above 180 mg/dL (72 and 40.0%, respectively, p < 0.01). Hospital LOS was significantly longer in patients with hyperglycemia ≥ 140 mg/dL as compared with those with normoglycemia (29.3 and 12.8 days, respectively, p < 0.01). This association remained significant when introduced in a linear regression analysis including diagnosis, decreased glomerular filtration rate (GFR) and hospitalization unit (p < 0.01). CONCLUSIONS: Hyperglycemia during hospitalization affects more than half of hospitalized patients and is associated with a longer length of stay.

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Background: Hyperglycemia during hospital stay is associated with adverse outcomes. Aim: To characterize the frequency of hyperglycemia in a tertiary hospital and to correlate it with length of hospital stay (LOS). Material and Methods: Review of medical records of hospitalized patients. Demographic data and laboratory data, previous diabetes mellitus (DM) history, current main diagnosis, unit of hospitalization and the two highest capillary blood glucose values from the analyzed period were recorded for each patient. LOS was obtained from electronic clinical records. Results: 210 subjects, aged 60 ± 19 years (104 women) were included. 113 patients (54%) developed hyperglycemia ≥ 140 mg/L. Thirty one percent of these had a previous history of diabetes and 29% had stress hyperglycemia (SHG). Patients with a history of DM had a higher average blood glucose than those with SHG (238.9 and 178.2 mg/dL, respectively, p < 0.01) and a greater percentage of cases with a blood glucose above 180 mg/dL (72 and 40.0%, respectively, p < 0.01). Hospital LOS was significantly longer in patients with hyperglycemia ≥ 140 mg/dL as compared with those with normoglycemia (29.3 and 12.8 days, respectively, p < 0.01). This association remained significant when introduced in a linear regression analysis including diagnosis, decreased glomerular filtration rate (GFR) and hospitalization unit (p < 0.01). Conclusions: Hyperglycemia during hospitalization affects more than half of hospitalized patients and is associated with a longer length of stay.

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Background Despite aggressive treatment aimed at lowering LDL cholesterol (LDL-C) levels with statins, there is a high residual prevalence of cardiovascular diseases, which may depend on plasma cholesterol transported in other atherogenic lipoproteins. Aims To describe non-HDL cholesterol (non-HDL-C) levels in the Chilean population and their association with diabetes mellitus and cardiovascular disease. To evaluate compliance with non-HDL-C therapeutic goals -according to individual cardiovascular risk- at different levels of triglycerides, in comparison with LDL-C goal achievement. Material and Methods: We analyzed data from 2,792 Chilean subjects aged ≥ 15 years who were included in the 2009-2010 National Health Survey and had valid data for blood lipids, diabetes, and cardiovascular disease. Results Forty five percent of subjects had high non-HDL-C levels. The proportion of diabetic and non-diabetic subjects with high non-HDL-C levels was 81 and 42%, respectively (p < 0.01). A significant discordance was observed in the achievement of therapeutic objectives when LDL-C or non-HDL-C levels were considered, particularly in presence of triglycerides ≥ 150 mg/dl. Namely, 8% of the population showed elevated levels of high non-HDL-C despite adequate LDL-C levels. Conclusions Evaluation and management of elevated non-HDL-C in patients with adequate levels of LDL-C seems worthwhile considering the discordance observed between these blood cholesterol fractions. This strategy may be effective to reduce the residual cardiovascular risk in the Chilean population.

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Background Despite aggressive treatment aimed at lowering LDL cholesterol (LDL-C) levels with statins, there is a high residual prevalence of cardiovascular diseases, which may depend on plasma cholesterol transported in other atherogenic lipoproteins. Aims To describe non-HDL cholesterol (non-HDL-C) levels in the Chilean population and their association with diabetes mellitus and cardiovascular disease. To evaluate compliance with non-HDL-C therapeutic goals -according to individual cardiovascular risk- at different levels of triglycerides, in comparison with LDL-C goal achievement. Material and Methods: We analyzed data from 2,792 Chilean subjects aged ≥ 15 years who were included in the 2009-2010 National Health Survey and had valid data for blood lipids, diabetes, and cardiovascular disease. Results Forty five percent of subjects had high non-HDL-C levels. The proportion of diabetic and non-diabetic subjects with high non-HDL-C levels was 81 and 42%, respectively (p < 0.01). A significant discordance was observed in the achievement of therapeutic objectives when LDL-C or non-HDL-C levels were considered, particularly in presence of triglycerides ≥ 150 mg/dl. Namely, 8% of the population showed elevated levels of high non-HDL-C despite adequate LDL-C levels. Conclusions Evaluation and management of elevated non-HDL-C in patients with adequate levels of LDL-C seems worthwhile considering the discordance observed between these blood cholesterol fractions. This strategy may be effective to reduce the residual cardiovascular risk in the Chilean population.

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Diabetes Mellitus (DM) and obesity are a public health problem in Chile. Bariatric surgery is the most effective treatment alternative to achieve a significant and sustained weight reduction in patients with morbid obesity. The results of controlled clinical trials indicate that, compared to medical treatment, surgery for obese patients with DM2 allows a better control of blood glucose and cardiovascular risk factors, reduces the need for medications and increases the likelihood for remission. Consensus conferences and clinical practice guidelines support bariatric surgery as an option to treat DM2 in Class III Obesity (Body Mass Index (BMI) > 40) regardless of the glycemic control and the complexity of pharmacological treatment and in Class II Obesity (BMI 35-39,9) with inadequate glycemic control despite optimal pharmacological treatment and lifestyle. However, surgical indication for patients with DM2 and BMI between 30-34.9, the most prevalent sub-group, is only suggested. The Chilean Societies of Endocrinology and Diabetes and of Bariatric and Metabolic Surgery decided to generate a consensus regarding the importance of other factors related to DM2 that would allow a better selection of candidates for surgery, particularly when weight does not constitute an indication. Considering the national reality, we also need a statement regarding the selection and characteristics of the surgical procedure as well as the role of the diabetologist in the multidisciplinary team.

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BACKGROUND/OBJECTIVES: Abdominal obesity (AO) is associated with elevated risk for cardiovascular diseases; however, this association is less clear for non-obese people. We estimated the association of AO and cardiovascular risk factors (CVRF) and disease in non-obese adult individuals from Chile. SUBJECTS/METHODS: 5248 adults (15 years of age or older) of both sexes from the Chilean National Health Survey (October 2009 -September 2010, response rate 85%.) were included. Information on myocardial infarction and stroke was self-reported. BMI, waist circumference (WC), arterial pressure, plasma glucose, and cholesterol levels were measured. Predictive accuracy of WC was evaluated by area under curve of receiver operating characteristic analysis and cut off points were established by Youden Index. Relationship between AO and CVRF was analyzed by Chi-squared tests. RESULTS: Normal weight/overweight/obesity were present in 34.4%/45.2%/18.1% of men and 33.4%/33.6%/27.5% of women. Predictive accuracy of WC to identify at least one CVRF was 0.70/0.67 and optimal cutoff points for WC in non-obese subjects were 91/83 cm in men/women, respectively. AO was present in 98.2%/99.1% of obese, 70.5%/77.4% of overweight and 12.4%/16.4% of normal weight men/women. AO was associated with increased frequency of CVRF in overweight men (6/8 and stroke) and women (4/8) and higher frequency in normal weight men (8/8 and myocardial infarction/stroke) and women (6/8 and myocardial infarction). CONCLUSIONS: WC cutoff points calculated for non-obese chilean population discriminate more differences in CVRF in normal weight woman. AO significantly increases the frequency of CVRF and diseases in overweight and especially normal weight individuals. WC can be used as a low cost, feasible and reproducible predictor for CVRF in non-obese individuals in most clinical settings.

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Diabetes Mellitus (DM) and obesity are a public health problem in Chile. Bariatric surgery is the most effective treatment alternative to achieve a significant and sustained weight reduction in patients with morbid obesity. The results of controlled clinical trials indicate that, compared to medical treatment, surgery for obese patients with DM2 allows a better control of blood glucose and cardiovascular risk factors, reduces the need for medications and increases the likelihood for remission. Consensus conferences and clinical practice guidelines support bariatric surgery as an option to treat DM2 in Class III Obesity (Body Mass Index (BMI) > 40) regardless of the glycemic control and the complexity of pharmacological treatment and in Class II Obesity (BMI 35-39,9) with inadequate glycemic control despite optimal pharmacological treatment and lifestyle. However, surgical indication for patients with DM2 and BMI between 30-34.9, the most prevalent sub-group, is only suggested. The Chilean Societies of Endocrinology and Diabetes and of Bariatric and Metabolic Surgery decided to generate a consensus regarding the importance of other factors related to DM2 that would allow a better selection of candidates for surgery, particularly when weight does not constitute an indication. Considering the national reality, we also need a statement regarding the selection and characteristics of the surgical procedure as well as the role of the diabetologist in the multidisciplinary team.

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Antecedentes: Las dislipidemias, ya sea un aumento en los niveles de colesterol LDL y/o una disminución en las cifras de colesterol HDL, son muy relevantes para el desarrollo de la enfermedad cardiovascular ateroesclerótica, siendo el colesterol HDL bajo la dislipidemia más frecuente en la población chilena. Con respecto al colesterol HDL bajo y los tri -glicéridos elevados, los fibratos, agonistas del receptor nuclear PPAR-a que modula la transcripción de genes involucrados en el metabolismo de lípidos, representan una importante alternativa de manejo farmacológico de las dislipidemias. Sin embargo, estudios clínicos recientes no han sido concluyentes con respecto a su beneficio real sobre el control de la ateroesclerosis cuando se usan combinados con estatinas. Objetivo: Evaluar el impacto de la administración de fibratos sobre el metabolismo del colesterol HDL y la función antioxidante del plasma usando el ratón como modelo experimental. Metodología: Los ratones de la cepa C57BL/6 fueron tratados con ciprofibrato al 0,2% en dieta control durante 7 días. Luego del tratamiento, se analizaron los niveles de colesterol plasmático y triglicéridos, la expresión hepática de proteínas claves involucradas en el metabolismo de colesterol HDL, el contenido de colesterol hepático, la secreción de colesterol biliar y el daño oxidativo y la función antioxidante plasmática. Resultados: El tratamiento con ciprofibrato disminuyó significativamente los niveles de triglicéridos plasmáticos y la expresión hepática del receptor de HDL SR-BI, efecto que se correlacionó con un aumento en el tamaño de las partículas de HDL, pero no en los niveles de colesterol HDL. Además, el ciprofibrato disminuyó los niveles proteicos de los transportadores de colesterol ABCG1 y ABCG8, aunque no modificó ABCA1, en conjunto con una reducción del contenido hepático de colesterol y un aumento en la secreción de colesterol hacia la bilis. Finalmente, el uso de este hipolipemiante mejoró la función antioxidante del plasma, aunque se detectó un aumento en el daño nitrosativo de las proteínas plasmáticas. Conclusión: Este estudio ha permitido obtener nueva información sobre el efecto metabólico y funcional de la administración de fibratos en ratones, lo cual podría ayudar comprender los resultados de estudios clínicos recientes que han usado esta clase de hipolipemiantes en humanos.

Background: Increased serum levels of LDL cholesterol and/or decreased values of HDL cholesterol are very relevant for atherosclerotic cardiovascular disease. Low HDL cholesterol is the most prevalent dyslipidemia in the Chilean population. Regarding reduced HDL cholesterol and high triglyceride levels, fibrates, nuclear receptor PPAR-a agonists that modulate transcription of genes involved in lipid metabolism, represent an important alternative for pharmacological management of dyslipidemia. However, recent clinical studies have been inconclusive with respect to their real benefit on atherosclerosis when used in combination with statins. Aim: To evaluate the impact of fibrate administration on HDL cholesterol metabolism and antioxidant plasma functionality using the mouse as experimental model. Methodology: Using wild-type C57BL/6 mice, ciprofibrate was administered at 0.2% in chow diet for 7 days. After treatment, plasma cholesterol and triglycerides levels, hepatic expression of key proteins involved in HDL cholesterol metabolism, liver cholesterol content, biliary cholesterol secretion, and plasma oxidative damage and antioxidant function were analyzed. Results: Ciprofibrate treatment significantly decreased plasma triglycerides levels and hepatic HDL receptor SR-BI expression. This latter finding was associated with increased HDL particle size, without changes in HDL cholesterol levels. Furthermore, ci-profibrate decreased hepatic expression of cholesterol transporters ABCG1 and ABCG8, but not ABCA1, which correlated with reduced liver cholesterol content and increased biliary cholesterol secretion. Fina-lly, fibrate therapy improved plasma antioxidant func-tion, even though increased nitrosative plasma protein damage was detected. Conclusion: This study has provided new information on metabolic and functional effects derived from fibrate use in mice and it may help to better understand recent clinical findings using this lipid-lowering drug class in humans.

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BACKGROUND: Plasma high density lipoproteins (HDL) are involved in reverse cholesterol transport mediated by the scavenger receptor class B type I (SR-BI). Nicotinic acid increases HDL cholesterol levels, even though its specific impact on SR-BI dependent-cellular cholesterol transport remains unknown. AIM: To determine the effect of nicotinic acid on HDL particle functionality in cholesterol efflux and uptake mediated by SR-BI in cultured cells in hypoalphalipoproteinemic patients. MATERIAL AND METHODS: In a pilot study, eight patients with low HDL (≤ 40 mg/dL) were treated with extended release nicotinic acid. HDL cholesterol and phospholipid levels, HDL2 and HDL3 fractions and HDL particle sizes were measured at baseline and post-therapy. Before and after nicotinic acid treatment, HDL particles were used for cholesterol transport studies in cells transfected with SR-BI. RESULTS: Nicotinic acid treatment raised total HDL cholesterol and phospholipids, HDL2 levels as well as HDL particle size. Nicotinic acid significantly increased HDL cholesterol efflux and uptake capacity mediated by SR-BI in cultured cells. CONCLUSIONS: Nicotinic acid therapy increases SR-BI-dependent HDL cholesterol transport in cultured cells, establishing a new cellular mechanism by which this lipid-lowering drug appears to modulate HDL metabolism in patients with hypoalphalipoproteinemia.

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Background: Plasma high density lipoproteins (HDL) are involved in reverse cholesterol transport mediated by the scavenger receptor class B type I (SR-BI). Nicotinic acid increases HDL cholesterol levels, even though its specific impact on SR-BI dependent-cellular cholesterol transport remains unknown. Aim: To determine the effect of nicotinic acid on HDL particle functionality in cholesterol efflux and uptake mediated by SR-BI in cultured cells in hypoalphalipoproteinemic patients. Material and Methods: In a pilot study, eight patients with low HDL (≤ 40 mg/dL) were treated with extended release nicotinic acid. HDL cholesterol and phospholipid levels, HDL2 and HDL3 fractions and HDL particle sizes were measured at baseline and post-therapy. Before and after nicotinic acid treatment, HDL particles were used for cholesterol transport studies in cells transfected with SR-BI. Results: Nicotinic acid treatment raised total HDL cholesterol and phospholipids, HDL2 levels as well as HDL particle size. Nicotinic acid significantly increased HDL cholesterol efflux and uptake capacity mediated by SR-BI in cultured cells. Conclusions: Nicotinic acid therapy increases SR-BI-dependent HDL cholesterol transport in cultured cells, establishing a new cellular mechanism by which this lipid-lowering drug appears to modulate HDL metabolism in patients with hypoalphalipoproteinemia.

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Insulin resistance is a prevalent condition commonly associated with unhealthy lifestyles. It affects several metabolic pathways, increasing risk of abnormalities at different organ levels. Thus, diverse medical specialties should be involved in its diagnosis and treatment. With the purpose of unifying criteria about this condition, a scientific-based consensus was elaborated. A questionnaire including the most important topics such as cardio-metabolic risk, non-alcoholic fatty liver disease and polycystic ovary syndrome, was designed and sent to national experts. When no agreement among them was achieved, the Delphi methodology was applied. The main conclusions reached are that clinical findings are critical for the diagnosis of insulin resistance, not being necessary blood testing. Acquisition of a healthy lifestyle is the most important therapeutic tool. Insulin-sensitizing drugs should be prescribed to individuals at high risk of disease according to clinically validated outcomes. There are specific recommendations for pregnant women, children, adolescents and older people.

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Cerebrotendinous Xanthomatosis (CTX), a rare lipid storage disorder, is caused by recessive loss-of-function mutations of the 27-sterol hydroxylase (CYP27A1), producing an alteration of the synthesis of bile acids, with an accumulation of cholestanol. Clinical characteristics include juvenile cataracts, diarrhea, tendon xanthomas, cognitive impairment and other neurological manifestations. Early diagnosis is critical, because treatment with chenodeoxycholic acid may prevent neurological damage. We studied the CYP27A1 gene in two Chilean CTX patients by sequencing its nine exons, exon-intron boundaries, and cDNA from peripheral blood mononuclear cells. Patient 1 is a compound heterozygote for the novel substitution c.256-1G > T that causes exon 2 skipping, leading to a premature stop codon in exon 3, and for the previously-known pathogenic mutation c.1183C > T (p.Arg395Cys). Patient 2 is homozygous for the novel mutation c.1185-1G > A that causes exon 7 skipping and the generation of a premature stop codon in exon 8, leading to the loss of the crucial adrenoxin binding domain of CYP27A1.

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Insulin resistance is a prevalent condition commonly associated with unhealthy lifestyles. It affects several metabolic pathways, increasing risk of abnormalities at different organ levels. Thus, diverse medical specialties should be involved in its diagnosis and treatment. With the purpose of unifying criteria about this condition, a scientific-based consensus was elaborated. A questionnaire including the most important topics such as cardio-metabolic risk, non-alcoholic fatty liver disease and polycystic ovary syndrome, was designed and sent to national experts. When no agreement among them was achieved, the Delphi methodology was applied. The main conclusions reached are that clinical findings are critical for the diagnosis of insulin resistance, not being necessary blood testing. Acquisition of a healthy lifestyle is the most important therapeutic tool. Insulin-sensitizing drugs should be prescribed to individuals at high risk of disease according to clinically validated outcomes. There are specific recommendations for pregnant women, children, adolescents and older people.

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Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease, caused by genetic deficiency of the 27-hydroxylase enzyme (encoded by CYP27A1). It plays a key role in cholesterol metabolism, especially in bile acid synthesis and in the 25-hydroxylation of vitamin D3 in the liver. Its deficiency causes reduced bile acid synthesis and tissue accumulation of cholestanol. Clinical manifestations are related to the presence of cholestanol deposits and include tendon xanthomas, premature cataracts, chronic diarrhea, progressive neurologic impairment and less frequently coronary heart disease, early onset osteoporosis and abnormalities in the optic disk and retina. An early diagnosis and treatment with quenodeoxycholic acid may prevent further complications, mainly neurological manifestations. This review summarizes cholesterol metabolism related to bile acid synthesis, physiopathology, biochemistry and treatment of cerebrotendinous xanthomatosis.

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BACKGROUND: Diabetes mellitus (DM) is a recognized atherosclerotic cardiovascular disease (ACVD) risk factor. This association has yet to be quantified in the Chilean population. AIM: To compare the frequency of ACVD between diabetic and non-diabetic Chilean subjects. MATERIAL AND METHODS: Data was extracted from the Chile National Health Survey (ENS) performed in 2009-2010. DM diagnosis was made with fasting glucose. ACVD (coronary, cerebral and peripheral vascular disease) was established by self-report. Major cardiovascular risk factors were identified by clinical and laboratory assessment. RESULTS: A total of 5,416 adults (2,200 men and 3,216 women) were surveyed in ENS 2009-2010. Of these, 508 were diabetic and 375 reported ACVD. ACVD frequency was 16.1% and 6.1% in diabetic and non-diabetic subjects, respectively. In diabetic men, the frequency of ACVD steadily increased with age, from 5.1% to 22.1%. In diabetic women, the highest frequency of ACVD (17.4%) was found in ages ranging from 45 to 54 years. In people younger than 54 years, the odds ratio for ACVD in diabetic compared to non-diabetic subjects, was 3.59 in men (χ2 = 4.03 p < 0.03) and 5.26 in women (χ2 = 7.7 p < 0.007). Cardiovascular risk factors and metabolic syndrome were significantly more common in diabetic subjects with reported ACVD. CONCLUSIONS: DM is associated with an increased frequency of ACVD and cardiovascular risk factors in Chilean adults. In line with international reports, our findings suggest that DM is also a cardiovascular risk factor in Chile, particularly relevant for women.

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Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease, caused by genetic deficiency of the 27-hydroxylase enzyme (encoded by CYP27A1). It plays a key role in cholesterol metabolism, especially in bile acid synthesis and in the 25-hydroxylation of vitamin D3 in the liver. Its deficiency causes reduced bile acid synthesis and tissue accumulation of cholestanol. Clinical manifestations are related to the presence of cholestanol deposits and include tendon xanthomas, premature cataracts, chronic diarrhea, progressive neurologic impairment and less frequently coronary heart disease, early onset osteoporosis and abnormalities in the optic disk and retina. An early diagnosis and treatment with quenodeoxycholic acid may prevent further complications, mainly neurological manifestations. This review summarizes cholesterol metabolism related to bile acid synthesis, physiopathology, biochemistry and treatment of cerebrotendinous xanthomatosis.

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Background: Diabetes mellitus (DM) is a recognized atherosclerotic cardiovascular disease (ACVD) risk factor. This association has yet to be quantified in the Chilean population. Aim: To compare the frequency of ACVD between diabetic and non-diabetic Chilean subjects. Material and Methods: Data was extracted from the Chile National Health Survey (ENS) performed in 2009-2010. DM diagnosis was made with fasting glucose. ACVD (coronary, cerebral and peripheral vascular disease) was established by self-report. Major cardiovascular risk factors were identified by clinical and laboratory assessment. Results: A total of 5,416 adults (2,200 men and 3,216 women) were surveyed in ENS 2009-2010. Of these, 508 were diabetic and 375 reported ACVD. ACVD frequency was 16.1% and 6.1% in diabetic and non-diabetic subjects, respectively. In diabetic men, the frequency of ACVD steadily increased with age, from 5.1% to 22.1%. In diabetic women, the highest frequency of ACVD (17.4%) was found in ages ranging from 45 to 54 years. In people younger than 54 years, the odds ratio for ACVD in diabetic compared to non-diabetic subjects, was 3.59 in men (χ2 = 4.03 p < 0.03) and 5.26 in women (χ2 = 7.7 p < 0.007). Cardiovascular risk factors and metabolic syndrome were significantly more common in diabetic subjects with reported ACVD. Conclusions: DM is associated with an increased frequency of ACVD and cardiovascular risk factors in Chilean adults. In line with international reports, our findings suggest that DM is also a cardiovascular risk factor in Chile, particularly relevant for women.

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Cholesterol has evolved to fulfill sophisticated biophysical, cell signaling and endocrine requirements of animal systems. At a cellular level, cholesterol is found in membranes, where it increases both bilayer stiffness and impermeability to water and ions. Furthermore, cholesterol is integrated into specialized lipid-protein membrane microdomains with critical topographical and signaling functions. At an organismal level, cholesterol is the precursor for all steroid hormones, including gluco- and mineralo-corticoids, sex hormones and vitamin D, all of which regulate carbohydrate, sodium, reproductive and bone homeostasis, respectively. This sterol is also the precursor for bile acids, which are important for intestinal absorption of dietary lipids as well as energy and glucose metabolic regulation. Importantly, complex mechanisms maintain cholesterol within physiological ranges and the disregulation of these mechanisms results in embryonic or adult diseases, caused by either excessive or reduced tissue cholesterol levels. The causative role of cholesterol in these diseases has been demonstrated by diverse genetic and pharmacologic animal models that are commented in this review.

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Cholesterol has evolved to fulfill sophisticated biophysical, cell signalling, and endocrine functions in animal systems. At the cellular level, cholesterol is found in membranes where it increases both bilayer stiffness and impermeability to water and ions. Furthermore, cholesterol is integrated into specialized lipid-protein membrane microdomains with critical topographical and signalling functions. At the organismal level, cholesterol is the precursor of all steroid hormones, including gluco- and mineralo-corticoids, sex hormones, and vitamin D, which regulate carbohydrate, sodium, reproductive, and bone homeostasis, respectively. This sterol is also the immediate precursor of bile acids, which are important for intestinal absorption of dietary lipids as well as energy homeostasis and glucose regulation. Complex mechanisms maintain cholesterol within physiological ranges and the dysregulation of these mechanisms results in embryonic or adult diseases, caused by either excessive or reduced tissue cholesterol levels. The causative role of cholesterol in these conditions has been demonstrated by genetic and pharmacological manipulations in animal models of human disease that are discussed herein. Importantly, the understanding of basic aspects of cholesterol biology has led to the development of high-impact pharmaceutical therapies during the past century. The continuing effort to offer successful treatments for prevalent cholesterol-related diseases, such as atherosclerosis and neurodegenerative disorders, warrants further interdisciplinary research in the coming decades.

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BACKGROUND: Severe hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family. METHODS: We carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives. RESULTS: A large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls. CONCLUSION: The Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family.

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