Project description:The ketogenic diet has been successful in promoting weight loss among patients that have struggled with weight gain. This is due to the cellular switch in metabolism that utilizes liver-derived ketone bodies for the primary energy source rather than glucose. Fatty acid transport protein 2 (FATP2) is highly expressed in liver, small intestine, and kidney where it functions in both the transport of exogenous long chain fatty acids (LCFA) and in the activation to CoA thioesters of very long chain fatty acids (VLCFA). We have completed a multi-omic study of FATP2-null (Fatp2-/-) mice maintained on a ketogenic diet (KD) or paired control diet (CD), with and without a 24-hour fast (KD-fasted and CD-fasted) to address the impact of deleting FATP2 under high-stress conditions. Control (wt/wt) and Fatp2-/- mice were maintained on their respective diets for 4-weeks. Afterwards, half the population was sacrificed while the remaining were fasted for 24-hours prior to sacrifice. We then performed paired-end RNA-sequencing on the whole liver tissue to investigate differential gene expression. The differentially expressed genes mapped to ontologies such as the metabolism of amino acids and derivatives, fatty acid metabolism, protein localization, and components of the immune system’s complement cascade, and were supported by the proteome and histological staining.
Project description:The aim of this study was to assess whether chronic treatment with RPV can modulate the progression of chronic liver disease, especially of non-alcoholic fatty liver disease (NAFLD), through a nutritional model in wild-type mice Mice were daily treated with RPV (p.o.) and fed with normal or high fat diet during 3 months to induce fatty liver disease
Project description:Liver tumors had high levels of histone acetylation. Nrf2 knockout mice developed fewer tumors than Nrf2 wild-type mice. The mechanistic study found that Nrf2 knockout reduced the generation of acetyl CoA from impaired glycolysis, TCA cycle, and fatty acid metabolism. Acetyl CoA is the substrate for protein acetylation including histone acetylation. Here we determined the genome-wide distribution of AcH3K27. We found that Nrf2 through regulating acetyl CoA production affects histone acetylation (AcH3K27) to modulate the expression of genes, whose products were involved in the glycolysis, TCA cycle, fatty acid metabolism, and oncogenic Myc/mTor signaling. Our findings supported an Nrf2-integrated metabolic, epigenetic and oncogenic signaling in driving liver tumor development.
Project description:We identified the gene Far2, encoding the fatty acyl-coA reductase 2, to be associated with mesangial matrix expansion (MME) in the mouse (PMID: 24009241). In order to verify this association we obtained the C57BL/6N-Far2tm2a(KOMP)Wtsi/2J (JR#018805) strain from The Jackson Laboratory's KOMP2 program and compared this strain to it's control strain (C57BL/6N) for several renal characteristics. At 6 months of age the knockout mice have a significantly better kidney function (measured as glomerular filtration rate) but the MME is at a comparable level. However, as MME increases in the control strain at 12 months of age, MME does not increase in the knockout until 18 months of age. In order to explore changes at the gene expression level, we compared RNA sequence reads from 6-month old kidneys. Our analysis showed a decrease of RNA expression for several tubular damage markers (NGAL, KIM-1) and an increase in several genes in the fatty acid metabolism pathway.
Project description:Acetaminophen is a widely used antipyretic and analgesic drug, and its overdose is the leading cause of drug-induced acute liver failure. This study aimed to investigate the effect and mechanism of Lacticaseibacillus casei Shirota (LcS), an extensively used and highly studied probiotic, on acetaminophen-induced acute liver injury. C57BL/6 mice were gavaged with LcS suspension or saline once daily for 7 days before the acute liver injury was induced via intraperitoneal injection of 300 mg/kg acetaminophen. The results showed that LcS significantly decreased acetaminophen-induced liver and ileum injury, as demonstrated by reductions in the increases in aspartate aminotransferase, total bile acids, total bilirubin, indirect bilirubin and hepatic cell necrosis. Moreover, LcS alleviated the acetaminophen-induced intestinal mucosal permeability, elevation in serum IL-1α and lipopolysaccharide, and decreased levels of serum eosinophil chemokine (eotaxin) and hepatic glutathione levels. Furthermore, analysis of the gut microbiota and metabolome showed that LcS reduced the acetaminophen-enriched levels of Cyanobacteria, Oxyphotobacteria, long-chain fatty acids, cholesterol and sugars in the gut. Additionally, the transcriptome and proteomics showed that LcS mitigated the downregulation of metabolism and immune pathways as well as glutathione formation during acetaminophen-induced acute liver injury. This is the first study showing that pretreatment with LcS alleviates acetaminophen-enriched acute liver injury, and it provides a reference for the application of LcS.
Project description:Fatty acid transport protein 2 (FATP2) is highly expressed in liver, small intestine, and kidney where it functions in both the uptake of exogenous long chain fatty acids (LCFAs) and in the activation to CoA thioesters of very long chain fatty acids (VLCFAs). Here we address the phenotypic impacts of deleting FATP2 followed by an unbiased RNA-seq analysis of the liver transcriptome. Wild type (C57BL/6J) and fatp2 null (fatp2-/-) mice (5 weeks old) were maintained on a standard chow diet for 6 weeks (11 weeks old). The male fatp2-/- mice had 258 differentially expressed genes (DEGs) and the female mice had a total of 91. Of significance was the finding that most of the genes with increased expression in the fatp2-/- liver are regulated by the transcription factor peroxisome proliferator-activated receptor alpha (PPARα). Taken together, FATP2 has a broad impact on the expression of key lipid metabolic genes in the liver regulated by PPARα.
Project description:Real-time quantitative PCR analysis of fatty acid metabolism genes of liver tissue from wild-type and PPARα (-/-) mice exposed to 2,4-dinitrotoluene (fatty acid)
Project description:SILAC based protein correlation profiling using size exclusion of protein complexes derived from Mus musculus tissues (Heart, Liver, Lung, Kidney, Skeletal Muscle, Thymus)
Project description:Introgressed variants from other species can be an important source of genetic variation because they may arise rapidly, can include multiple mutations on a single haplotype, and have often been pretested by selection in the species of origin. Although introgressed alleles are generally deleterious, several studies have reported introgression as the source of adaptive alleles-including the rodenticide-resistant variant of Vkorc1 that introgressed from Mus spretus into European populations of Mus musculus domesticus. Here, we conducted bidirectional genome scans to characterize introgressed regions into one wild population of M. spretus from Spain and three wild populations of M. m. domesticus from France, Germany, and Iran. Despite the fact that these species show considerable intrinsic postzygotic reproductive isolation, introgression was observed in all individuals, including in the M. musculus reference genome (GRCm38). Mus spretus individuals had a greater proportion of introgression compared with M. m. domesticus, and within M. m. domesticus, the proportion of introgression decreased with geographic distance from the area of sympatry. Introgression was observed on all autosomes for both species, but not on the X-chromosome in M. m. domesticus, consistent with known X-linked hybrid sterility and inviability genes that have been mapped to the M. spretus X-chromosome. Tract lengths were generally short with a few outliers of up to 2.7 Mb. Interestingly, the longest introgressed tracts were in olfactory receptor regions, and introgressed tracts were significantly enriched for olfactory receptor genes in both species, suggesting that introgression may be a source of functional novelty even between species with high barriers to gene flow.