Biology subjects

Saikali, M. F.

Publications and source records attributed to Saikali, M. F..

4 recordsLinked to original sources

bioRxiv2026

Liver-specific loss of the transcriptional coregulator ARGLU1 protects against diet-induced obesity in mice through decreased lipid absorption

New medications that decrease food intake show promise in addressing the global obesity epidemic; however, additional therapies are needed for patients who are intolerant or unresponsive to these drugs. ARGLU1 is a transcriptional coregulator of several nuclear receptors. Herein, we detail the discovery that mice lacking ARGLU1 in hepatocytes (LKO) are resistant to diet-induced obesity, with no difference in food intake, locomotion, or energy expenditure compared to wildtype mice. Interestingly, LKO mice exhibited decreased CYP8B1, corresponding to fewer 12-hydroxylated bile acids, increasing the relative hydrophobicity of bile which decreases lipid emulsification. Notably, LKO mice have lower plasma and liver cholesterol levels, attributed to impaired lipid absorption. Furthermore, LKO mice showed preferential use of fatty acids as their fuel source. Herein, we establish a mechanistic basis for resistance of ARGLU1 LKO mice to diet-induced obesity, identifying a potential new molecular target for obesity.

physiology↗

bioRxiv2025

MetaboMiNR: a web application to analyze label free quantitative proteomic experiments with a focus on metabolism and nuclear receptors

Label free quantitative (LFQ) proteomics is growing in popularity and becoming increasingly more accessible to researchers, empowering them to compare proteome-wide changes between different treatment conditions. However, it remains difficult to leverage the full potential of LFQ data when the researcher has limited experience in proteomics and/or bioinformatics due to the complexity of data analysis. Here, we present MetaboMiNR, an easy-to-use web application for the analysis of LFQ data with a focus on metabolism and nuclear receptors. MetaboMiNR guides users through an intuitive process with clear instructions and minimal user input to conduct statistical analysis and produce publication ready plots. Users may input a MaxQuant generated output file and perform standard global analysis and data quality control with the click of a button. The application offers 3 additional unique features: 1) Metabolism Miner extracts a user selected Reactome pathway from the dataset, 2) Nuclear Receptor Miner extracts the target genes of a user-selected nuclear receptor, and 3) Individual Plotter produces publication-ready bar plots for a selected protein. The utility of this application was demonstrated by analyzing a previously published dataset from mice treated with LDT409, a synthetic PPAR agonist. MetaboMiNR can be accessed freely at https://cumminslab.shinyapps.io/MetaboMiNR/.

bioinformatics↗

bioRxiv2021

Splicing Factor SRSF1 Deficiency in the Liver Triggers NASH-like Pathology via R-Loop Induced DNA Damage and Cell Death

Regulation of RNA processing contributes profoundly to tissue development and physiology. Here, we report that serine-arginine-rich splicing factor 1 (SRSF1) is essential for hepatocyte function and survival. Although SRSF1 is mainly known for its many roles in mRNA metabolism, it is also crucial for maintaining genome stability. We show that acute liver damage in the setting of targeted SRSF1 deletion in mice is primarily mediated by the excessive formation of deleterious RNA-DNA hybrids (R-loops), which induce DNA damage. Combining hepatocyte-specific transcriptome, proteome, and RNA binding analyses, we demonstrate that widespread genotoxic stress following SRSF1 depletion results in global inhibition of mRNA transcription and protein synthesis, leading to impaired metabolism and trafficking of lipids. Lipid accumulation in SRSF1-deficient hepatocytes is followed by necroptotic cell death, inflammation, and fibrosis, resulting in NASH-like liver pathology. Importantly, SRSF1-depleted human liver cancer cells recapitulate this pathogenesis illustrating a conserved and fundamental role for SRSF1 in preserving genome integrity and tissue homeostasis. Thus, our study uncovers how accumulation of detrimental R-loops impedes hepatocellular gene expression, triggering metabolic derangements and liver failure.

cell biology↗

bioRxiv2021

Akr1d1-/- mice have a sexually dimorphic metabolic phenotype with reduced fat mass, increased insulin sensitivity and hypertriglyceridemia in males

BackgroundSteroid 5{beta}-reductase (AKR1D1) plays important roles in hepatic glucocorticoid clearance and bile acid synthesis. Glucocorticoids and bile acids are potent metabolic regulators, but whether AKR1D1 controls metabolic phenotype in vivo is unknown. MethodsAkr1d1-/-mice were generated on a C57BL/6 background. Liquid chromatography / mass spectrometry, metabolomic and transcriptomic approaches were used to determine effects on glucocorticoid and bile acid homeostasis. Metabolic phenotypes including body weight and composition, lipid homeostasis, glucose tolerance and insulin sensitivity were evaluated. Molecular changes were assessed by RNASeq and western blotting. Male Akr1d1-/-mice were challenged with a 60% high fat diet. ResultsAkr1d1-/-mice had a sex specific metabolic phenotype. At 30-weeks of age male, but not female, Akr1d1-/-mice were more insulin sensitive and had reduced lipid accumulation in the liver and adipose tissue, concomitant with hypertriglyceridemia and increased intramuscular triacylglycerol. This phenotype was underpinned by sexually dimorphic changes in bile acid metabolism and composition, but without overt effects on glucocorticoid action. Male Akr1d1-/-mice were not protected against diet induced obesity and insulin resistance. ConclusionThis study shows that AKR1D1 controls bile acid homeostasis in vivo and that altering its activity can affect insulin sensitivity and lipid homeostasis in a sex dependent manner.

physiology↗