APOA5
Apolipoprotein A-V precursor (Apo-AV) (ApoA-V) (Apolipoprotein A5) (Regeneration-associated protein 3) [RAP3] [UNQ411/PRO773]
Publications[править]
Objective- APOA5 variants are strongly associated with hypertriglyceridemia, as well as increased risks of cardiovascular disease and acute pancreatitis. Hypertriglyceridemia in apo AV dysfunction often aggravates by environmental factors such as high-carbohydrate diets or aging. To date, the molecular mechanisms by which these environmental factors induce hypertriglyceridemia are poorly defined, leaving the high-risk hypertriglyceridemia condition undertreated. Previously, we reported that LXR (liver X receptor)-SREBP (sterol regulatory element-binding protein)-1c pathway regulates large-VLDL (very low-density lipoprotein) production induced by LXR agonist. However, the pathophysiological relevance of the finding remains unknown. Approach and Results- Here, we reconstitute the environment-induced hypertriglyceridemia phenotype of human APOA5 deficiency in Apoa5 mice and delineate the role of SREBP-1c in vivo by generating Apoa5 ;Srebp-1c mice. The Apoa5 mice, which showed moderate hypertriglyceridemia on a chow diet, developed severe hypertriglyceridemia on high-carbohydrate feeding or aging as seen in patients with human apo AV deficiency. These responses were nearly completely abolished in the Apoa5 ;Srebp-1c mice. Further mechanistic studies revealed that in response to these environmental factors, SREBP-1c was activated to increase triglyceride synthesis and to permit the incorporation of triglyceride into abnormally large-VLDL particles, which require apo AV for efficient clearance. Conclusions- Severe hypertriglyceridemia develops only when genetic factors (apo AV deficiency) and environmental effects (SREBP-1c activation) coexist. We demonstrate that the regulated production of large-sized VLDL particles via SREBP-1c determines plasma triglyceride levels in apo AV deficiency. Our findings explain the long-standing enigma of the late-onset hypertriglyceridemia phenotype of apo AV deficiency and suggest a new approach to treat hypertriglyceridemia by targeting genes that mediate environmental effects.
MeSH Terms
- Aging
- Animal Feed
- Animals
- Apolipoprotein A-V
- Apolipoproteins
- Chylomicrons
- Female
- Fructose
- Gene Expression Regulation
- Gene-Environment Interaction
- Humans
- Hydrocarbons, Fluorinated
- Hypertriglyceridemia
- Lipids
- Lipoproteins, VLDL
- Liver X Receptors
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Models, Animal
- Olive Oil
- Sterol Regulatory Element Binding Protein 1
- Sulfonamides
Keywords
- carbohydrate
- diet
- hypertriglyceridemia
- phenotype
- sterol regulatory element-binding protein
We aimed to evaluate whether the longitudinal interaction between APOA5-1131C variants and overweight could accelerate age-related increases in arterial stiffness and circulating triglycerides in healthy subjects. This 3-year prospective cohort study included 503 healthy subjects. Brachial-ankle pulse wave velocity (baPWV), triglycerides, APOA5 -1131T > C, apolipoprotein (apo) A-V level, and low-density lipoprotein (LDL) particle size were measured at baseline and within a mean follow-up period of 3 years. At the 3-year follow-up, in the overweight group, subjects with the C allele showed increases in triglycerides and baPWV relative to baseline. Additionally, in the overweight group, there was a genotype effect on changes in triglycerides: subjects with the C allele had greater increases in triglyceride concentrations than subjects with the TT genotype. Furthermore, overweight subjects with the C allele had greater increases in triglyceride concentrations than normal-weight subjects with the C allele (P-interaction = 0.013). Overweight subjects with the C allele had greater increases in baPWV than normal-weight subjects with the C allele (P-interaction = 0.047). Changes in baPWV were affected by age, baseline baPWV, and changes in systolic blood pressure (BP) and triglycerides. Changes in triglycerides were affected by APOA5 -1131T > C genotype, age, baseline triglyceride level, and changes in BMI and apo A-V. In the overweight group, changes in baPWV were affected by changes in systolic BP, LDL particle size, and triglycerides. This prospective study shows that the interactive effect between APOA5 -1131C variants and overweight can accelerate age-related increase in arterial stiffness via the regulation of circulating triglycerides in healthy subjects.
MeSH Terms
- Adult
- Aged
- Aging
- Alleles
- Ankle Brachial Index
- Apolipoprotein A-V
- Blood Pressure
- Female
- Follow-Up Studies
- Gene Frequency
- Gene-Environment Interaction
- Genotype
- Humans
- Male
- Middle Aged
- Overweight
- Polymorphism, Single Nucleotide
- Pulse Wave Analysis
- Triglycerides
- Vascular Stiffness
Keywords
- APOA5
- Arterial stiffness
- Gene-environment interaction
- Overweight
- Triglycerides
The plasma levels of high-density lipoprotein cholesterol (HDL) have an inverse relationship to the risks of atherosclerosis and cardiovascular disease (CVD), and have also been associated with longevity. We sought to identify novel loci for HDL that could potentially provide new insights into biological regulation of HDL metabolism in healthy-longevous subjects. We performed a genome-wide association (GWA) scan on HDL using a mixed model approach to account for family structure using kinship coefficients. A total of 4114 subjects of European descent (480 families) were genotyped at ~2.3 million SNPs and ~38 million SNPs were imputed using the 1000 Genome Cosmopolitan reference panel in MACH. We identified novel variants near-NLRP1 (17p13) associated with an increase of HDL levels at genome-wide significant level (p < 5.0E-08). Additionally, several CETP (16q21) and ZNF259-APOA5-A4-C3-A1 (11q23.3) variants associated with HDL were found, replicating those previously reported in the literature. A possible regulatory variant upstream of NLRP1 that is associated with HDL in these elderly Long Life Family Study (LLFS) subjects may also contribute to their longevity and health. Our NLRP1 intergenic SNPs show a potential regulatory function in Encyclopedia of DNA Elements (ENCODE); however, it is not clear whether they regulate NLRP1 or other more remote gene. NLRP1 plays an important role in the induction of apoptosis, and its inflammasome is critical for mediating innate immune responses. Nlrp1a (a mouse ortholog of human NLRP1) interacts with SREBP-1a (17p11) which has a fundamental role in lipid concentration and composition, and is involved in innate immune response in macrophages. The NLRP1 region is conserved in mammals, but also has evolved adaptively showing signals of positive selection in European populations that might confer an advantage. NLRP1 intergenic SNPs have also been associated with immunity/inflammasome disorders which highlights the biological importance of this chromosomal region.
Keywords
- NALP1
- aging
- familial longevity
- family-based study
- genomewide association study
- lipids