DRAM1
DNA damage-regulated autophagy modulator protein 1 (Damage-regulated autophagy modulator) [DRAM]
Publications[править]
Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10 ) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.
MeSH Terms
- Aged
- Aging
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO
- Cohort Studies
- Energy Intake
- European Continental Ancestry Group
- Female
- Fibroblast Growth Factors
- Genetic Loci
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Genomics
- Genotype
- Heart Diseases
- Humans
- Male
- Membrane Proteins
- Middle Aged
- Nutrients
- Obesity
- Polymorphism, Single Nucleotide
- Receptors, Retinoic Acid
Autophagy is an evolutionarily conserved catabolic mechanism that relieves cellular stress by removing/recycling damaged organelles and debris through the action of lysosomes. Compromised autophagy has been implicated in many neurodegenerative diseases, including retinal degeneration. Here we examined retinal phenotypes resulting from RPE-specific deletion of the autophagy regulatory gene Atg7 by generating Atg7(flox/flox);VMD2-rtTA-cre mice to determine whether autophagy is essential for RPE functions including retinoid recycling. Atg7-deficient RPE displayed abnormal morphology with increased RPE thickness, cellular debris and vacuole formation indicating that autophagy is important in maintaining RPE homeostasis. In contrast, 11-cis-retinal content, ERGs and retinal histology were normal in mice with Atg7-deficient RPE in both fasted and fed states. Because A2E accumulation in the RPE is associated with pathogenesis of both Stargardt disease and age-related macular degeneration (AMD) in humans, deletion of Abca4 was introduced into Atg7(flox/flox);VMD2-rtTA-cre mice to investigate the role of autophagy during A2E accumulation. Comparable A2E concentrations were detected in the eyes of 6-month-old mice with and without Atg7 from both Abca4(-/-) and Abca4( / ) backgrounds. To identify other autophagy-related molecules involved in A2E accumulation, we performed gene expression array analysis on A2E-treated human RPE cells and found up-regulation of four autophagy related genes; DRAM1, NPC1, CASP3, and EIF2AK3/PERK. These observations indicate that Atg7-mediated autophagy is dispensable for retinoid recycling and A2E deposition; however, autophagy plays a role in coping with stress caused by A2E accumulation.
MeSH Terms
- Animals
- Autophagy-Related Protein 7
- Cell Line
- Eye Proteins
- Gene Deletion
- Humans
- Macular Degeneration
- Mice
- Mice, Transgenic
- Microtubule-Associated Proteins
- Retinal Pigment Epithelium
- Retinoids
- Stargardt Disease
- Ubiquitin-Activating Enzymes
- Vision, Ocular
Keywords
- A2E
- ABCA4
- Stargardt disease
- aging
- autophagy
- autophagy-related protein 7 (ATG7)
- retina
- retinal degeneration