ABSTRACT
Plasma lipids are modulated by gene variants and many environmental factors, including diet-associated weight gain. However, understanding how these factors jointly interact to influence molecular networks that regulate plasma lipid levels is limited. Here, we took advantage of the BXD recombinant inbred family of mice to query weight gain as an environmental stressor on plasma lipids. Coexpression networks were examined in both nonobese and obese livers, and a network was identified that specifically responded to the obesogenic diet. This obesity-associated module was significantly associated with plasma lipid levels and enriched with genes known to have functions related to inflammation and lipid homeostasis. We identified key drivers of the module, including Cidec, Cidea, Pparg, Cd36, and Apoa4. The Pparg emerged as a potential master regulator of the module as it can directly target 19 of the top 30 hub genes. Importantly, activation of this module is causally linked to lipid metabolism in humans, as illustrated by correlation analysis and inverse-variance weighed Mendelian randomization. Our findings provide novel insights into gene-by-environment interactions for plasma lipid metabolism that may ultimately contribute to new biomarkers, better diagnostics, and improved approaches to prevent or treat dyslipidemia in patients.
Subject(s)
Diet, High-Fat , Gene Regulatory Networks , Humans , Mice , Animals , Diet, High-Fat/adverse effects , PPAR gamma/genetics , Obesity/genetics , Obesity/metabolism , Weight Gain , LipidsABSTRACT
SCOPE: The molecular mechanisms whereby gallates in green tea exert metabolic effects are poorly understood. METHODS AND RESULTS: We found that GPRC6A, a multi-ligand-sensing G-protein-coupled receptor that regulates energy metabolism, sex hormone production, and prostate cancer progression, is a target for gallates. Sodium gallate (SG), gallic acid (GA) > ethyl gallate (EG) > octyl gallate (OG) dose dependently activated ERK in HEK-293 cells transfected with GPRC6A but not in non-transfected controls. SG also stimulated insulin secretion in ß-cells isolated from wild-type mice similar to the endogenous GPRC6A ligands, osteocalcin (Ocn) and testosterone (T). Side-chain additions to create OG resulted in loss of GPRC6A agonist activity. Another component of green tea, epigallocatechin 3-gallate (EGCG), dose-dependently inhibited Ocn activation of GPRC6A in HEK-293 cells transfected with GPRC6A and blocked the effect of Ocn in stimulating glucose production in CH10T1/2 cells. Using structural models of the venus fly trap (VFT) and 7-transmembrane (7-TM) domains of GPRC6A, calculations suggest that l-amino acids and GA bind to the VFT, whereas EGCG is calculated to bind to sites in both the VFT and 7-TM. CONCLUSION: GA and EGCG have offsetting agonist and antagonist effects on GPRC6A that may account for the variable metabolic effect of green tea consumption.
Subject(s)
Catechin/analogs & derivatives , Gallic Acid/metabolism , Incretins/metabolism , Insulin Secretion , Kidney/metabolism , Models, Molecular , Receptors, G-Protein-Coupled/metabolism , Animals , Binding Sites , Catechin/chemistry , Catechin/metabolism , Cells, Cultured , Computational Biology , Dietary Supplements , Gallic Acid/analogs & derivatives , Gallic Acid/chemistry , Gene Expression Regulation , HEK293 Cells , Humans , MAP Kinase Signaling System , Mice , Molecular Conformation , Molecular Docking Simulation , Molecular Dynamics Simulation , RNA Interference , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/genetics , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Tea/chemistryABSTRACT
Evaluation of graft-host bone interactions after failed vascularized fibular grafting of femoral head necrosis may elucidate the reasons for failure of the procedure. According to the authors' study, the vascularized fibula implanted into the femoral head before collapse has the potential for restructuring the major segment of the affected head and delaying joint degeneration for many years if circumferential graft-host union is established. Asymmetric bone healing and non-union between the graft and the necrotic subchondral bone in the weight-bearing area lead to failure, progression of symptoms, and subsequent early hip replacement.