Biology subjects

Haid, M.

Publications and source records attributed to Haid, M..

3 recordsLinked to original sources

bioRxiv2026

Oxysterol-sensing by Liver X receptor counteracts ferroptosis via lipid remodeling

Ferroptosis, an iron-dependent form of regulated cell death, is controlled by cellular metabolism. Nutrients and metabolites determine cell states that render cells sensitive or resistant to ferroptosis. Nuclear receptors can act as cellular sensors for distinct metabolites and nutrients to regulate ferroptosis. We performed a chemical genetics screen using a nuclear receptor small molecule library to identify novel regulators of ferroptosis. We find that activating or overexpressing the liver X receptor (LXR) suppresses ferroptosis in various cell models, including ex vivo primary mouse hepatocytes. Interestingly, hepatocellular carcinoma with high levels of LXR shows poorer survival outcomes. In cells, activation of LXR by the endogenous oxysterol 24(S),25-epoxycholesterol or synthetic agonists reduces lipid peroxidation and ferroptotic cell death. Mechanistically, LXR activation drives a selective transcriptional program upregulating SREBP-1c, SCD1 and ACSL3, key enzymes involved in the synthesis of monounsaturated fatty acid-containing phospholipids (MUFA-PLs). Lipidomic analysis reveals that this lipid remodeling enriches cellular membranes with MUFA-PLs, reducing their susceptibility to peroxidation and thereby counteracting ferroptosis. Together, we identify LXR as an oxysterol-sensing endogenous suppressor of ferroptosis coupling oxysterol sensing to the adaptive remodeling of cellular membrane lipid composition to limit lipid peroxidation.

cell biology↗

bioRxiv2024

Housing temperature dictates the systemic and tissue specific molecular responses to cancer in mice

Cancer cachexia is a metabolic condition affecting up to 80% of patients with cancer. Cachexia is mediated by reduced muscle and fat mass and impaired function, and it lowers survival for patients. With no approved drugs to treat cachexia, preclinical efforts focus on understanding the molecular mechanisms underlying this condition to reveal treatment targets. Housing laboratory mice at ambient temperature imposes cold stress, leading to induced thermogenic activity and consequent whole-body metabolic adaptations. Yet, the impact of housing temperature in in vivo preclinical cachexia remains unknown. We found that thermoneutral (TN) housing in C26 carcinoma-bearing (C26) mice affected lean and fat mass, but not muscle weight or force. TN housing improved glucose tolerance in C26 mice, while enhancing circulating abundance of FGF21 and IL-6. Thermogenic tissues, especially brown adipose tissue, exhibited housing temperature-dependent molecular responses to cancer in oxygen consumption, ATP levels and SERCA ATPase activity, which are all crucial for cancer-induced whole-body metabolic adaptations. We conclude that molecular and systemic adaptations to cancer in mice critically depend on housing temperature, which should be considered in the design and interpretation of preclinical cancer studies.

physiology↗

bioRxiv2019

Characterization of bulk phosphatidylcholine compositions in human plasma using side-chain resolving lipidomics

Kit-based assays, such as AbsoluteIDQ p150, are widely used in large cohort studies and provide a standardized method to quantify blood concentrations of phosphatidylcholines (PCs). Many disease-relevant associations of PCs were reported using this method. However, their interpretation is hampered by lack of functionally relevant information on the detailed fatty acid side chain compositions as only the total number of carbon atoms and double bonds is identified by the kit. To enable more substantiated interpretations, we characterized these PC sums using the side chain resolving Lipidyzer platform, analyzing 223 samples in parallel to the AbsoluteIDQ. Combining these datasets, we estimated the quantitative composition of PC sums and subsequently tested their replication in an independent cohort. We identified major constituents of 28 PC sums, revealing also various unexpected compositions. As an example, PC 16:0_22:5 accounted for more than 50% of the PC sum with in total 38 carbon atoms and 5 double bonds (PC aa 38:5). For 13 PC sums, we found relatively high abundances of odd-chain fatty acids. In conclusion, our study provides insights in PC compositions in human plasma, facilitating interpretation of existing epidemiological datasets and potentially enabling imputation of PC compositions for future meta-analyses of lipidomics data.

epidemiology↗