Biology subjects

Wittung-Stafshede, P.

Publications and source records attributed to Wittung-Stafshede, P..

2 recordsLinked to original sources

bioRxiv2022

Comparing lipid remodeling in mouse adipose and liver tissue with quantitative Raman microscopy

Brown adipose tissue (BAT) consists of highly metabolically active adipocytes that catabolize nutrients to produce heat. Playing an active role in triacylglycerol (TAG) clearance, research has shown that dietary fatty acids can modulate the TAG chemistry deposition in BAT after weeks-long dietary intervention, similar to what has been shown in white adipose tissue (WAT). Our objective was to compare the influence of sustained, non-chronic dietary intervention (a one-week interval) on WAT and BAT lipid metabolism and deposition in situ. We use quantitative, label-free chemical microscopy to show that one week of HFD intervention results in dramatically larger lipid droplet (LD) growth in BAT (and liver) compared to LD growth in inguinal WAT (IWAT). Moreover, BAT showed lipid remodeling as increased unsaturated TAGs in LDs, resembling the dietary lipid composition, while WAT (and liver) did not show lipid remodeling on this time scale. Concurrently, expression of genes involved in lipid metabolism, particularly desaturases, was reduced in BAT and liver from HFD-fed mice after one week. Our data show that BAT lipid chemistry remodels exceptionally fast to dietary lipid intervention compared WAT, which further points towards a role in TAG clearance.

cell biology↗

bioRxiv2020

Structural and molecular determinants of CCS-mediated copper activation of MEK1/2

SummaryNormal physiology relies on the precise coordination of intracellular signal transduction pathways that respond to nutrient availability to balance cell growth and cell death. We recently established a critical mechanistic function for the redox-active micronutrient copper (Cu) in the canonical mitogen activated protein kinase (MAPK) pathway at the level of MEK1 and MEK2. Here we report the X-ray crystal structure of Cu-MEK1 and reveal active site chemical ligands and oxidation state specificity for MEK1 Cu coordination. Mechanistically, the Cu chaperone CCS selectively bound to and facilitated Cu transfer to MEK1. Mutations in MEK1 that disrupt Cu(I) affinity or a CCS small molecule inhibitor reduced Cu-stimulated MEK1 kinase activity. These atomic and molecular level data provide the first mechanistic insights of Cu kinase signaling and could be exploited for the development of novel MEK1/2 inhibitors that either target the Cu structural interface or blunt dedicated Cu delivery mechanisms via CCS.Competing Interest StatementD.C.B holds ownership in Merlon Inc. D.C.B. is an inventor on the patent application 20150017261 entitled Methods of treating and preventing cancer by disrupting the binding of copper in the MAP kinase pathway. No potential conflicts of interest were disclosed by the other authors.View Full Text

biochemistry↗