Sustained phenotypic correction in a mouse model of hypoalphalipoproteinemia with a helper-dependent adenovirus vector. (1/17)
We examined the efficacy and host response to the adenovirus (Ad)-mediated delivery of human apolipoprotein A-I (APOA1) gene to the liver of APOA1(-/-) mice. Administration of a first-generation vector (FGAd-AI) resulted in a transient appearance of APOA1 in plasma and induced an anti-APOA1 antibody titer, whereas treatment with a helper-dependent vector (HDAd-AI) resulted in sustained APOA1 expression without inducing an antibody titer. With these results, we studied the effects of FGAd vectors on APOAI expression by HDAd-AI vector. Co-treatment with an FGAd vector inhibited HDAd-AI- mediated APOA1 expression independent of transgene cassettes, but only FGAd-AI induced a humoral response. Furthermore, APOA1 mRNA levels in mice co-treated with FGAd vectors were much lower than those expected from the vector copy number, suggesting that DNA of FGAd vectors interferes with the HDAd-AI vector's APOA1 promoter. A single treatment with an HDAd-AI vector produced a supraphysiological plasma APOA1 level that gradually declined to about half the normal human level over the course of 2 years, associated with a plasma cholesterol level that is persistently higher than that in controls. This investigation provides the proof of principle that liver-directed HDAd gene delivery is effective for the long-term phenotypic correction of monogenic hypoalphalipoproteinemia. (+info)The ATP-binding cassette transporter A1 R230C variant affects HDL cholesterol levels and BMI in the Mexican population: association with obesity and obesity-related comorbidities. (2/17)
Although ATP-binding cassette transporter A1 (ABCA1) is well known for its role in cholesterol efflux and HDL formation, it is expressed in various tissues, where it may have different functions. Because hypoalphalipoproteinemia is highly prevalent in Mexico, we screened the ABCA1 coding sequence in Mexican individuals with low and high HDL cholesterol levels to seek functional variants. A highly frequent nonsynonymous variant (R230C) was identified in low-HDL cholesterol but not in high-HDL cholesterol individuals (P = 0.00006). We thus assessed its frequency in the Mexican-Mestizo general population, seeking possible associations with several metabolic traits. R230C was screened in 429 Mexican Mestizos using Taqman assays, and it was found in 20.1% of these individuals. The variant was significantly associated not only with decreased HDL cholesterol and apolipoprotein A-I levels but also with obesity (odds ratio 2.527, P = 0.005), the metabolic syndrome (1.893, P = 0.0007), and type 2 diabetes (4.527, P = 0.003). All of these associations remained significant after adjusting for admixture (P = 0.011, P = 0.001, and P = 0.006, respectively). This is the first study reporting the association of an ABCA1 variant with obesity and obesity-related comorbidities as being epidemiologically relevant in the Mexican population. (+info)Genetic-epidemiological evidence on genes associated with HDL cholesterol levels: a systematic in-depth review. (3/17)
(+info)Multiple splice defects in ABCA1 cause low HDL-C in a family with hypoalphalipoproteinemia and premature coronary disease. (4/17)
(+info)Identification of a novel human cellular HDL biosynthesis defect. (5/17)
(+info)Total and high molecular weight adiponectin have similar utility for the identification of insulin resistance. (6/17)
(+info)Prevalence of dyslipidemias in the Mexican National Health and Nutrition Survey 2006. (7/17)
(+info)Lipid profile of schoolchildren from Recife, PE. (8/17)
(+info)Hypoalphalipoproteinemia is a condition characterized by decreased levels of alpha-lipoproteins, particularly the alpha-1 lipoprotein called high-density lipoprotein (HDL), in the blood. HDL plays a crucial role in removing excess cholesterol from tissues and carrying it back to the liver for excretion or recycling. Low levels of HDL are considered a risk factor for developing cardiovascular diseases, such as atherosclerosis, because they may lead to an accumulation of cholesterol in the blood vessels.
There are different types and causes of hypoalphalipoproteinemias, including:
1. Familial Hypoalphalipoproteinemia (FHA): An inherited condition characterized by low HDL levels due to mutations in the APOA1, APOC3, or ABCA1 genes, which are involved in HDL metabolism. FHA is often associated with an increased risk of premature cardiovascular disease.
2. Tangier Disease: A rare genetic disorder caused by mutations in the ABCA1 gene, leading to extremely low HDL levels and the accumulation of cholesterol deposits in various tissues, including the liver, spleen, and nerves. Tangier disease is characterized by enlarged, orange-colored tonsils, neuropathy, and an increased risk of cardiovascular diseases.
3. Secondary Hypoalphalipoproteinemia: Low HDL levels can also be caused by secondary factors such as obesity, physical inactivity, smoking, diabetes mellitus, chronic kidney disease, hypothyroidism, nephrotic syndrome, and the use of certain medications (e.g., corticosteroids, progestins, and beta-blockers).
In summary, hypoalphalipoproteinemia refers to a group of conditions characterized by decreased levels of alpha-lipoproteins, particularly HDL, in the blood. This can be due to genetic factors or secondary causes and may increase the risk of developing cardiovascular diseases.