Biology subjects

Mejhert, N.

Publications and source records attributed to Mejhert, N..

5 recordsLinked to original sources

bioRxiv2024

Defining the Vascular Niche of Human Adipose Tissue Across Metabolic Conditions

IntroductionAdipose tissue homeostasis depends on a healthy vascular network. Vascular malfunction is a hallmark of obesity1, and vascular endothelial dysfunction, in particular, accelerates metabolic diseases, including obesity and diabetes. Single-cell transcriptomics studies have mapped the cellular landscape of human white adipose tissue (WAT)2-8. However, the vascular niche remains relatively undefined9, especially regarding its heterogeneity, function, and role in metabolic disease. To address this gap, we created a single-cell transcriptome atlas of human subcutaneous adipose tissue (SAT), comprising nearly 70,000 vascular cells from 65 individuals. We characterized seven canonical adipose tissue endothelial cell (AdEC) subtypes and identified a distinct heterogenous population, here referred to as sub-AdECs. Sub-AdECs exhibit gene signatures characteristic of multiple cell types, including mesenchymal, adipocytic, and immune, suggesting they possess diverse properties and identities. Through computational analyses and whole-mount imaging, we validated the occurrence of sub-AdECs and show that these cells likely arise through endothelial-mesenchymal transition (EndMT), the modulation of which limits obesity-associated adipose tissue inflammation and fibrosis. Furthermore, we compared the transcriptomes of vascular cells from individuals living with or without obesity and type 2 diabetes and find metabolic disease-associated inflammatory and fibrotic transcriptomic patterns. The atlas and accompanying analyses establish a solid foundation for investigations into the biology of the adipose tissue vascular niche and its contribution to the pathogenesis of metabolic disease.

cell biology↗

bioRxiv2023

A Spatiotemporal Proteomic Map of Human Adipogenesis

White adipocytes function as the major energy reservoir in humans by storing substantial amounts of triglycerides and their dysfunction is associated with metabolic disorders. However, the mechanisms underlying cellular specialization during adipogenesis remain unknown. Here, using a high-sensitivity-high throughput workflow, we generated a spatiotemporal proteomic atlas of human adipogenesis encompassing information for ~8.000 proteins. Our systematic approach gives insights into cellular remodeling and the spatial reorganization of metabolic pathways to optimize cells for lipid accumulation and highlights the coordinated regulation of protein localization and abundance during adipogenesis. More specifically, we identified a compartment-specific regulation of protein levels and localization changes of metabolic enzymes to reprogram branched chain amino acid and one-carbon metabolism to provide building blocks and reduction equivalents for lipid synthesis. Additionally, we identified C19orf12 as a differentiation induced and adipocyte-specific lipid droplet (LD) protein, which interacts with the translocase of the outer membrane (TOM) complex of LD associated mitochondria and regulates adipocyte lipid storage. Overall, our study provides a comprehensive resource for understanding human adipogenesis and for future discoveries in the field. KEY POINTSO_LIHuman adipogenesis induces distinct temporal changes in protein abundance C_LIO_LI20% of all detected proteins change organellar localization during adipogenesis C_LIO_LIBCAA and one-carbon metabolism enzyme levels and localizations are coordinately regulated to promote adipogenesis C_LIO_LIC19orf12 is an adipocyte specific LD protein and regulator of lipid storage C_LI

molecular biology↗

bioRxiv2021

The Lipid Droplet Knowledge Portal: A resource for systematic analyses of lipid droplet biology

Lipid droplets (LDs) are organelles of cellular lipid storage with fundamental roles in energy metabolism and cell membrane homeostasis. There has been an explosion of research into the biology of LDs, in part due to their relevance in diseases of lipid storage, such as atherosclerosis, obesity, type 2 diabetes mellitus, and hepatic steatosis. Consequently, there is an increasing need for a resource that combines large datasets from systematic analyses of LD biology. Here we integrate high-confidence, systematically generated data on studies of LDs in the framework of an online platform named the Lipid Droplet Knowledge Portal. This scalable and interactive portal includes comprehensive datasets, across a variety of cell types, for LD biology, including transcriptional profiles of induced lipid storage, organellar proteomics, genome-wide screen phenotypes, and ties to human genetics. This new resource is a powerful platform that can be utilized to uncover new determinants of lipid storage. HIGHLIGHTS{blacksquare} The LD-Portal is a resource combining datasets from systematic analyses in LD biology {blacksquare}The LD-Portal allows users to query genetic, proteomic, and phenotypic aspects of LD biology {blacksquare}The LD-Portal can be used to discover new facets of lipid storage and LD biology {blacksquare}A crucial function of MSRB3 is uncovered in cholesterol ester storage in LDs

systems biology↗

bioRxiv2020

A Systematic Protein Turnover Map for Decoding Protein Degradation

Protein degradation is mediated by an expansive and complex network of protein modification and degradation enzymes. Matching degradation enzymes with their targets and determining globally which proteins are degraded by the proteasome or lysosome/vacuole has been a major challenge. Further, an integrated view of protein degradation for cellular pathways has been lacking. Here we present a novel analytical platform that combines systematic gene deletions with quantitative measures of protein turnover to deconvolve protein degradation pathways for S. cerevisiae. The resulting turnover map (T-MAP) reveals target candidates of nearly all E2 and E3 ubiquitin ligases and identifies the primary degradation routes for most proteins. We further mined this T-MAP to identify new substrates of ER-associated Degradation (ERAD) involved in sterol biosynthesis and to uncover novel regulatory nodes for sphingolipid biosynthesis. The T-MAP approach should be broadly applicable to the study of other cellular processes and systems, including mammalian systems. One Sentence SummaryA systematic, global map of protein turnover for a large set of yeast mutants reveals scope and specificity of degradation pathways and identifies novel regulatory nodes for lipid metabolism.

systems biology↗

bioRxiv2018

FIT2 is a lipid phosphate phosphatase crucial for endoplasmic reticulum homeostasis

The endoplasmic reticulum (ER) protein Fat-Induced Transcript 2 (FIT2) has emerged as a key factor in lipid droplet (LD) formation, although its molecular function is unknown. Highlighting its importance, FIT2 orthologs are essential in worms and mice, and FIT2 deficiency causes a deafness/dystonia syndrome in humans. Here we show that FIT2 is a lipid phosphate phosphatase (LPP) enzyme that is required for maintaining the normal structure of the ER. Recombinant FIT2 exhibits LPP activity in vitro and loss of this activity in cells leads to ER membrane morphological changes and ER stress. Defects in LD formation in FIT2 depletion appear to be secondary to membrane lipid abnormalities, possibly due to alterations in phospholipids required for coating forming LDs. Our findings uncover an enzymatic role for FIT2 in ER lipid metabolism that is crucial for ER membrane homeostasis.

cell biology↗