Knockout of the non-essential gene SUGCT creates diet-linked, age-related microbiome disbalance with a diabetes-like metabolic syndrome phenotype

Autor: Kia Ngee Low, Igor V. Kurochkin, Christine M. F. Goh, Matias J. Caldez, Vincenzo Coppola, Philipp Kaldis, Frank Eisenhaber, Yoganathan Kanagasundaram, Sebastian Maurer-Stroh, Hyungwon Choi, Lakshmi Gopinathan, Elisabeth Pfeiffenberger, Yang Lay Kien, Oliver S. Jones, Joanna Niska-Blakie, Chee Bing Ong, Lino Tessarollo
Rok vydání: 2019
Předmět:
Aging
Adipose tissue
Gut flora
Kidney
Feces
Mice
0302 clinical medicine
Sugct
Metabolic Syndrome
Mice
Knockout
0303 health sciences
Tryptophan
Phenotype
Lipids
Anti-Bacterial Agents
medicine.anatomical_structure
Liver
Glutaric aciduria type 3 (GA3)
Metabolome
Molecular Medicine
Original Article
C7orf10
medicine.medical_specialty
Biology
03 medical and health sciences
Cellular and Molecular Neuroscience
Internal medicine
Diabetes mellitus
Carnitine
medicine
Animals
Humans
Metabolomics
Microbiome
Obesity
Molecular Biology
030304 developmental biology
Pharmacology
Gut microflora
Bacteria
Lysine
Cell Biology
medicine.disease
biology.organism_classification
Lipid Metabolism
Gastrointestinal Microbiome
Endocrinology
Dietary Supplements
Metabolic syndrome
Coenzyme A-Transferases
Dysbiosis
030217 neurology & neurosurgery
Zdroj: Cellular and Molecular Life Sciences
ISSN: 1420-9071
Popis: SUGCT (C7orf10) is a mitochondrial enzyme that synthesizes glutaryl-CoA from glutarate in tryptophan and lysine catabolism, but it has not been studied in vivo. Although mutations in Sugct lead to Glutaric Aciduria Type 3 disease in humans, patients remain largely asymptomatic despite high levels of glutarate in the urine. To study the disease mechanism, we generated SugctKO mice and uncovered imbalanced lipid and acylcarnitine metabolism in kidney in addition to changes in the gut microbiome. After SugctKO mice were treated with antibiotics, metabolites were comparable to WT, indicating that the microbiome affects metabolism in SugctKO mice. SUGCT loss of function contributes to gut microbiota dysbiosis, leading to age-dependent pathological changes in kidney, liver, and adipose tissue. This is associated with an obesity-related phenotype that is accompanied by lipid accumulation in kidney and liver, as well as “crown-like” structures in adipocytes. Furthermore, we show that the SugctKO kidney pathology is accelerated and exacerbated by a high-lysine diet. Our study highlights the importance of non-essential genes with no readily detectable early phenotype, but with substantial contributions to the development of age-related pathologies, which result from an interplay between genetic background, microbiome, and diet in the health of mammals.
Databáze: OpenAIRE
Externí odkaz: