Liver Transcriptome Analysis Research Articles

Dietary Curcumin Supplementation Could Improve Muscle Quality, Antioxidant Enzyme Activities and the Gut Microbiota Structure of Pelodiscus sinensis.

This experiment aimed to assess the impact of different dietary curcumin (CM) levels on growth, muscle quality, serum-biochemical parameters, antioxidant-enzyme activities, gut microbiome, and liver transcriptome in Chinese soft-shelled turtles (Pelodiscus sinensis). Five experimental diets were formulated to include graded levels of curcumin at 0 (control, CM0), 0.5 (CM0.5), 1 (CM1), 2 (CM2) and 4 g/kg (CM4). Each diet was randomly distributed to quadruplicate groups of turtles (164.33 ± 5.5 g) for 6 weeks. Our findings indicated that dietary curcumin supplementation did not have a significant influence on growth performance (p > 0.05); however, it significantly improved the muscular texture profiles (p < 0.05). Serum total superoxide dismutase (SOD), liver catalase (CAT), and total antioxidant capacity (T-AOC) activities increased significantly as dietary curcumin levels rose from 0.5 to 4 g/kg (p < 0.05). Dietary curcumin supplementation improved gut microbiota composition, as evidenced by an increase in the proportion of dominant bacteria such as Lactobacillus and Flavobacterium. Liver transcriptome analysis revealed that curcumin altered metabolic pathways in the liver. In conclusion, based on the evaluation of the activities of SOD in serum and CAT in liver under current experimental design, it was determined that the appropriate dietary curcumin supplementation for Chinese soft-shelled turtles is approximately 3.9 g/kg.

Biliary atresia is associated with polygenic susceptibility in ciliogenesis and planar polarity effector genes

Biliary atresia (BA) is poorly understood and leads to liver transplantation (LT), with the requirement for and associated risks of lifelong immunosuppression, in most children. We performed a genome-wide association study (GWAS) to determine the genetic basis of BA. We performed a GWAS in 811 European BA cases treated with LT in US, Canadian and UK centers, and 4,654 genetically matched controls. Whole-genome sequencing of 100 cases evaluated synthetic association with rare variants. Functional studies included whole liver transcriptome analysis of 64 BA cases and perturbations in experimental models. A GWAS of common single nucleotide polymorphisms (SNPs), i.e. allele frequencies >1%, identified intronic SNPs rs6446628 in AFAP1 with genome-wide significance (p= 3.93E-8) and rs34599046 in TUSC3 at sub-threshold genome-wide significance (p= 1.34E-7), both supported by credible peaks of neighboring SNPs. Like other previously reported BA-associated genes, AFAP1 and TUSC3 are ciliogenesis and planar polarity effectors (CPLANE). In gene-set-based GWAS, BA was associated with 6,005 SNPs in 102 CPLANE genes (p= 5.84E-15). Compared with non-CPLANE genes, more CPLANE genes harbored rare variants (allele frequency <1%) that were assigned Human Phenotype Ontology terms related to hepatobiliary anomalies by predictive algorithms, 87% vs. 40%, p <0.0001. Rare variants were present in multiple genes distinct from those with BA-associated common variants in most BA cases. AFAP1 and TUSC3 knockdown blocked ciliogenesis in mouse tracheal cells. Inhibition of ciliogenesis caused biliary dysgenesis in zebrafish. AFAP1 and TUSC3 were expressed in fetal liver organoids, as well as fetal and BA livers, but not in normal or disease-control livers. Integrative analysis of BA-associated variants and liver transcripts revealed abnormal vasculogenesis and epithelial tube formation, explaining portal vein anomalies that co-exist with BA. BA is associated with polygenic susceptibility in CPLANE genes. Rare variants contribute to polygenic risk in vulnerable pathways via unique genes. Liver transplantation is needed to cure most children born with biliary atresia, a poorly understood rare disease. Transplant immunosuppression increases the likelihood of life-threatening infections and cancers. To improve care by preventing this disease and its progression to transplantation, we examined its genetic basis. We find that this disease is associated with both common and rare mutations in highly specialized genes which maintain normal communication and movement of cells, and their organization into bile ducts and blood vessels during early development of the human embryo. Because defects in these genes also cause other birth defects, our findings could lead to preventive strategies to lower the incidence of biliary atresia and potentially other birth defects.

Transcriptomic regulations of heat stress response in the liver of lactating dairy cows

BackgroundThe global dairy industry is currently facing the challenge of heat stress (HS). Despite the implementation of various measures to mitigate the negative impact of HS on milk production, the cellular response of dairy cows to HS is still not well understood. Our study aims to analyze transcriptomic dynamics and functional changes in the liver of cows subjected to heat stress (HS). To achieve this, a total of 9 Holstein dairy cows were randomly selected from three environmental conditions - heat stress (HS), pair-fed (PF), and thermoneutral (TN) groups - and liver biopsies were obtained for transcriptome analysis.ResultsBoth the dry matter intake (DMI) and milk yield of cows in the HS group exhibited significant reduction compared to the TN group. Through liver transcriptomic analysis, 483 differentially expressed genes (DEGs) were identified among three experimental groups. Especially, we found all the protein coding genes in mitochondria were significantly downregulated under HS and 6 heat shock proteins were significant upregulated after HS exposure, indicating HS may affect mitochondria integrity and jeopardize the metabolic homeostasis in liver. Furthermore, Gene ontology (GO) enrichment of DEGs revealed that the protein folding pathway was upregulated while oxidative phosphorylation was downregulated in the HS group, corresponding to impaired energy production caused by mitochondria dysfunction.ConclusionsThe liver transcriptome analysis generated a comprehensive gene expression regulation network upon HS in lactating dairy cows. Overall, this study provides novel insights into molecular and metabolic changes of cows conditioned under HS. The key genes and pathways identified in this study provided further understanding of transcriptome regulation of HS response and could serve as vital references to mitigate the HS effects on dairy cow health and productivity.

Differential effects of bariatric surgery and caloric restriction on hepatic one-carbon and fatty acid metabolism

Weight loss interventions, including dietary changes, pharmacotherapy, or bariatric surgery, prevent many of the adverse consequences of obesity, and may also confer intervention-specific benefits beyond those seen with decreased weight alone. We compared the molecular effects of different interventions on liver metabolism to understand the mechanisms underlying these benefits. Male rats on a high-fat, high-sucrose diet underwent sleeve gastrectomy (SG) or intermittent fasting with caloric restriction (IF-CR), achieving equivalent weight loss. The interventions were compared to ad-libitum (AL)-fed controls. Analysis of liver and blood metabolome and transcriptome revealed distinct and sometimes contrasting metabolic effects between the two interventions. SG primarily influenced one-carbon metabolic pathways, whereas IF-CR increased de novo lipogenesis and glycogen storage. These findings suggest that the unique metabolic pathways affected by SG and IF-CR contribute to their distinct clinical benefits, with bariatric surgery potentially influencing long-lasting changes through its effect on one-carbon metabolism.

Dietary Cholesterol Supplementation Inhibits the Steroid Biosynthesis but Does Not Affect the Cholesterol Transport in Two Marine Teleosts: A Hepatic Transcriptome Study.

Cholesterol has been used as additive in fish feeds due to the reduced use of fish meal and fish oil. In order to evaluate the effects of dietary cholesterol supplementation (D-CHO-S) on fish physiology, a liver transcriptome analysis was performed following a feeding experiment on turbot and tiger puffer with different levels of dietary cholesterol. The control diet contained 30% fish meal (0% fish oil) without cholesterol supplementation, while the treatment diet was supplemented with 1.0% cholesterol (CHO-1.0). A total of 722 and 581 differentially expressed genes (DEG) between the dietary groups were observed in turbot and tiger puffer, respectively. These DEG were primarily enriched in signaling pathways related to steroid synthesis and lipid metabolism. In general, D-CHO-S downregulated the steroid synthesis in both turbot and tiger puffer. Msmo1, lss, dhcr24, and nsdhl might play key roles in the steroid synthesis in these two fish species. Gene expressions related to cholesterol transport (npc1l1, abca1, abcg1, abcg2, abcg5, abcg8, abcb11a, and abcb11b) in the liver and intestine were also extensively investigated by qRT-PCR. However, the results suggest that D-CHO-S rarely affected the cholesterol transport in both species. The protein-protein interaction (PPI) network constructed on steroid biosynthesis-related DEG showed that in turbot, Msmo1, Lss, Nsdhl, Ebp, Hsd17b7, Fdft1, and Dhcr7 had high intermediary centrality in the dietary regulation of steroid synthesis. In conclusion, in both turbot and tiger puffer, the supplementation of dietary cholesterol inhibits the steroid metabolism but does not affect the cholesterol transport.

A consortium of three-bacteria isolated from human feces inhibits formation of atherosclerotic deposits and lowers lipid levels in a mouse model

By a survey of metagenome-wide association studies (MWAS), we found a robust depletion of Bacteroides cellulosilyticus, Faecalibacterium prausnitzii, and Roseburia intestinalis in individuals with atherosclerotic cardiovascular disease (ACVD). From an established collection of bacteria isolated from healthy Chinese individuals, we selected B.cellulosilyticus, R.intestinalis, and Faecalibacterium longum, a bacterium related to F.prausnitzii, and tested the effects of these bacteria in an Apoe/- atherosclerosis mouse model. We show that administration of these three bacterial species to Apoe-/- mice robustly improves cardiac function, reduces plasma lipid levels, and attenuates the formation of atherosclerotic plaques. Comprehensive analysis of gut microbiota, plasma metabolome, and liver transcriptome revealed that the beneficial effects are associated with a modulation of the gut microbiota linked to a 7α-dehydroxylation-lithocholic acid (LCA)-farnesoid X receptor (FXR) pathway. Our study provides insights into transcriptional and metabolic impact whereby specific bacteria may hold promises for prevention/treatment of ACVD.

Effects of a High-Concentrate Diet on the Blood Parameters and Liver Transcriptome of Goats.

The objective of this study was to determine the effect of high-concentrate diets on the blood parameters and liver transcriptome of goats. Eighteen goats were allocated into three dietary treatments: the high level of concentrate (HC) group, the medium level of concentrate (MC) group, and the low level of concentrate (LC) group. The blood parameters and pathological damage of the gastrointestinal tract and liver tissues were measured. In hepatic portal vein blood, HC showed higher LPS, VFAs, and LA; in jugular vein blood, no significant differences in LPS, VFAs, and LA were recorded among groups (p > 0.05). Compared to the LC and MC groups, the HC group showed significantly increased interleukin (IL)-1β, IL-10, TNF-α, and diamine oxidase in jugular vein blood (p < 0.05). Liver transcriptome analysis discovered a total of 1269 differentially expressed genes (DEGs) among the three groups and most of them came from the HC vs. LC group. There were 333 DEGs up-regulated and 608 down-regulated in the HC group compared to the LC group. The gene ontology enrichment analysis showed that these DEGs were mainly focused on the regulation of triacylglycerol catabolism, lipoprotein particle remodeling, and cholesterol transport. The Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the liver of the HC group enhanced the metabolism of nutrients such as VFAs through the activation of AMPK and other signaling pathways and enhanced the clearance and detoxification of LPS by activating the toll-like receptor signaling pathway. A high-concentrate diet (HCD) can significantly promote the digestion of nutrients; the liver enhances the adaptability of goats to an HCD by regulating the expression of genes involved in nutrient metabolism and toxin clearance.

Generalized low levels of serum N-glycans associate with better health status.

Caloric restriction (CR) can prolong life and ameliorate age-related diseases; thus, its molecular basis might provide new insights for finding biomarker and intervention for aging and age-related disease. Glycosylation is an important post-translational modification, which can timely reflect the changes of intracellular state. Serum N-glycosylation was found changed with aging in humans and mice. CR is widely accepted as an effective anti-aging intervention in mice and could affect mouse serum fucosylated N-glycans. However, the effect of CR on the level of global N-glycans remains unknown. In order to explore whether CR affect the level of global N-glycans, we performed a comprehensive serum glycome profiling in mice of 30% calorie restriction group and ad libitum group at 7 time points across 60 weeks by MALDI-TOF-MS. At each time point, the majority of glycans, including galactosylated and high mannose glycans, showed a consistent low level in CR group. Interestingly, O-acetylated sialoglycans presented an upward change different from other derived traits, which is mainly reflected in two biantennary α2,6-linked sialoglycans (H5N4Ge2Ac1, H5N4Ge2Ac2). Liver transcriptome analysis further revealed a decreased transcriptional level of genes involved in N-glycan biosynthesis while increased level of acetyl-CoA production. This finding is consistent with changes in serum N-glycans and O-acetylated sialic acids. Therefore, we provided one possible molecular basis for the beneficial effect of CR from N-glycosylation perspective.

Transcriptomic Analysis of Liver in Silver sillago, Sillago sihama Fed with High-Level Low-Gossypol Cottonseed Meal in Replacement of Fishmeal Diet

Understanding the molecular mechanisms involved in adaptation to alternate diets has become a significant concern, as increasing amounts of fishmeal (FM) protein in aquafeeds are being substituted with plant protein. Thus, the goal of this study was to assess growth performance, quality, and liver function of juvenile Sillago sihama (S. sihama) through growth indices, whole-body composition, histology of the liver, and RNA-sequencing (RNA-seq), after they were fed a formulated diet with 64% low-gossypol cottonseed meal (LCSM) for 56 days, compared to those fed a traditional FM-based diet. Indicators of growth, including final body weight (FBW), weight gain rate (WGR), specific growth rate (SGR), protein efficiency ratio (PER), and condition factor (CF), were considerably lower in the 64% LCSM (R64) group than in the FM diet group. In the R64 diet, the whole crude lipid was significantly lower than in the FM diet. The hematoxylin-eosin section showed that dietary high levels of LCSM resulted in diffuse lipid vacuolation in the liver of S. sihama. According to a liver transcriptome analysis, high LCSM intake in the diet significantly impacted lipid synthesis and catabolism, elevated pathways for cholesterol synthesis, blocked several amino acid metabolic pathways, and adversely affected hepatic gluconeogenesis and glycolysis. The findings of this study indicate that feeding high levels of LCSM in S. sihama is harmful to the growth of the organism and can harm the liver's structural integrity, as well as obstruct the normal metabolism of amino acids, lipids, and carbohydrates. Therefore, it is not recommended to substitute LCSM for high levels of FM in the diet of S. sihama.

The effect of acute toxicity from tributyltin on Liza haematocheila liver: Energy metabolic disturbance, oxidative stress, and apoptosis

Tributyltin (TBT), a highly toxic and persistent organic pollutant, is widely distributed in coastal waters. Liza haematocheila (L. haematocheila) is one of bony fish distributing coincident with TBT, and exposure risk of TBT to this fish is unknown. In this study, L. haematocheila was exposed to TBT of 0, 3.4, 6.8, and 17.2 μg/L for 48 h to explore hepatic response mechanism. Our results showed that Sn content in livers increased after 48 h of exposure. HSI and histological changes indicated that TBT suppressed liver development of L. haematocheila. TBT reduced ATPase activities. The increased RB in blood and the reduced TBC were measured after exposure to TBT. T-AOC and antioxidant enzymes SOD, CAT, and GPx activities were inhibited while MDA content was increased. Liver cells showed apoptosis characteristics after TBT exposure. Furthermore, transcriptome analysis of livers was performed and the results showed energy metabolism-related GO term (such as ATPase complex and ATPase dependent transmembrance transport complex), oxidative stress-related GO term (such as Celllular response to oxidative stress and Antioxidant activity), and apoptosis-related GO term (such as Regulation of cysteine-type endopeptidase activity involved in apoptosic signaling pathway). Moreover, we found six energy metabolism-related differentially expressed genes (DEGs) including three up-regulated DEGs (atnb233, cftr, and prkag2) and three down-regulated DEGs (acss1, abcd2, and smarcb1); five oxidative stress-related DEGs including one up-regulated DEG (mmp9) and four down-regulated DEG (prdx5, hsp90, hsp98, and gstf9); as well as six apoptosis-related DEGs including five up-regulated DEGs (casp8, cyc, apaf1, hccs, and dapk3) and one down-regulated DEG (bcl2l1). Our transcriptome data above further confirmed that acute stress of TBT led energy metabolic disturbance, oxidative stress, and apoptosis in L. haematocheila livers.

Bamboo shoot dietary fiber alleviates gut microbiota dysbiosis and modulates liver fatty acid metabolism in mice with high-fat diet-induced obesity.

Obesity is a common nutritional disorder characterized by an excessive fat accumulation. In view of the critical role of gut microbiota in the development of obesity and metabolic diseases, novel dietary therapies have been developed to manage obesity by targeting the gut microbiome. In this study, we investigated anti-obesity effects of bamboo shoot dietary fiber (BSDF) and the potential mechanisms. After 12 weeks of intervention with BSDF in high-fat mice, we detected obesity-related phenotypic indicators, and made transcriptomic analysis of liver tissue. Then we analyzed the changes of gut microbiota using 16S rRNA gene sequencing, explored the effect of BSDF on gut microbiota metabolites, and finally verified the importance of gut microbiota through antibiotic animal model. We found that BSDF was effective in reducing lipid accumulation in liver and adipose tissue and alleviating dyslipidemia and insulin resistance. Liver transcriptome analysis results showed that BSDF could improve lipid metabolism and liver injury by modulating peroxisome proliferator-activated receptor (PPAR) and fatty acid metabolic pathways. The 16S rRNA gene sequencing analysis of gut microbiota composition showed that BSDF significantly enriched beneficial bacteria such as Bifidobacterium, Akkermansia, Dubosiella, and Alloprevotella. Analysis of fecal metabolomics and gut microbiota metabolites revealed that BSDF increased the levels of several short-chain fatty acids and enriched bile acids, which may be important for improving lipid metabolism. Notably, the obesity-related metabolic disorders were abrogated after the abrogation of gut microbiota, suggesting that gut microbiota is a key factor in the beneficial effects of BSDF. Our study suggests that BSDF as a prebiotic supplement has the potential to improve obesity by improving gut microbiota and modulating host PPAR and fatty acid metabolic pathways.

Transcriptome analysis of liver, gill and intestine in rainbow trout (Oncorhynchus mykiss) symptomatically or asymptomatically infected with Vibrio anguillarum

Rainbow trout (Oncorhynchus mykiss), an important economic cold-water fish worldwide, is severely threatened by viruses and bacteria in the farming industry. The vibriosis outbreak has caused a significant setback to aquaculture. Vibrio anguillarum, one of the common disease-causing vibriosis associated with severe lethal vibriosis in aquaculture, infects fish mainly by adsorption and invasion of the skin, gills, lateral line and intestine. To investigate the defense mechanism of rainbow trout against the pathogen after infection with Vibrio anguillarum, trout were intraperitoneally injected by Vibrio anguillarum and divided into symptomatic group (SG) and asymptomatic group (AG) according to the phenotype. RNA-Seq technology was used to evaluate the transcriptional signatures of liver, gill and intestine of trout injected with Vibrio anguillarum (SG and AG) and corresponding control groups (CG(A) and CG(B)). The GO and KEGG enrichment analyses were used to investigate the mechanisms underlying the differences in susceptibility to Vibrio anguillarum. Results showed that in SG, immunomodulatory genes in the cytokine network were activated and tissue function-related genes were down-regulated, while apoptosis mechanisms were activated. However, AG responded to Vibrio anguillarum infection by activating complement related immune defenses, while metabolism and function related genes were up-regulated. Conclusively, a rapid and effective immune and inflammatory response can successfully defend Vibrio anguillarum infection. However, a sustained inflammatory response can lead to tissue and organ damage and cause death. Our results may provide a theoretical basis for breeding rainbow trout for disease resistance.

Bile acid metabolism disorder mediates hepatotoxicity of Nafion by-product 2 and perfluorooctane sulfonate in male PPARα-KO mice

Perfluorooctane sulfonate (PFOS) and Nafion by-product 2 (H-PFMO2OSA) induce hepatotoxicity in male mice via activation of the peroxisome proliferator-activated receptor α (PPARα) pathway; however, accumulating evidence suggests that PPARα-independent pathways also play a vital role in hepatotoxicity after exposure to per- and polyfluoroalkyl substances (PFASs). Thus, to assess the hepatotoxicity of PFOS and H-PFMO2OSA more comprehensively, adult male wild-type (WT) and PPARα knockout (PPARα-KO) mice were exposed to PFOS and H-PFMO2OSA (1 or 5 mg/kg/d) for 28 d via oral gavage. Results showed that although elevations in alanine transaminase (ALT) and aspartate aminotransferase (AST) were alleviated in PPARα-KO mice, liver injury, including liver enlargement and necrosis, was still observed after PFOS and H-PFMO2OSA exposure. Liver transcriptome analysis identified fewer differentially expressed genes (DEGs) in the PPARα-KO mice than in the WT mice, but more DEGs associated with the bile acid secretion pathway after PFOS and H-PFMO2OSA treatment. Total bile acid content in the liver was increased in the 1 and 5 mg/kg/d PFOS-exposed and 5 mg/kg/d H-PFMO2OSA-exposed PPARα-KO mice. Furthermore, in PPARα-KO mice, proteins showing changes in transcription and translation levels after PFOS and H-PFMO2OSA exposure were involved in the synthesis, transportation, reabsorption, and excretion of bile acids. Thus, exposure to PFOS and H-PFMO2OSA in male PPARα-KO mice may disturb bile acid metabolism, which is not under the control of PPARα.

Liver transcriptome analysis and identification of differentially expressed immune gene response to Aeromonas veronii infection in Channa argus

Liver transcriptome analysis and identification of differentially expressed immune gene response to Aeromonas veronii infection in Channa argus

Liver Transcriptome Analysis Reveals Energy Regulation and Functional Impairment of Onychostoma simaDuring Starvation.

Releasing juvenile fish into resource-depleted waters is regarded as an effective way to restore fishery resources. However, during this stage, released fish are most vulnerable to long-term food deprivation due to environmental changes and low adaptability. Therefore, research regarding the energy regulation of fish under starvation stress is crucial to the optimization of release strategies. In this study, we performed a transcriptome analysis of the liver of Onychostoma sima subjected to starvation for 14days. The results showed that, under long-term starvation, the liver regulated glucose homeostasis by activating the gluconeogenesis pathway. Meanwhile, the fatty acid metabolism pathway was activated to supply acetyl-coA to the TCA cycle, thus increasing mitochondrial ATP production and maintaining the balance of energy metabolism. Nevertheless, the activation of energy metabolism could not completely compensate for the role of exogenous nutrients, as evidenced by the downregulation of many genes involved in antioxidant defenses (e.g., cat, gpx3, mgst1, and mgst2) and immune response (e.g., c3, cd22, trnfrsf14, and a2ml). In summary, our data reveal the effects of long-term starvation on the energy metabolism and defensive regulation of starved juvenile fish, and these findings will provide important reference for the optimization of artificial release.

Analyses of regulatory network and discovery of potential biomarkers for Korean rockfish (Sebastes schlegelii) in responses to starvation stress through transcriptome and metabolome

Whether in aquaculture or in nature, starvation stress limits the growth of fish. The purpose of the study was to clarify the detailed molecular mechanisms underlying starvation stress in Korean rockfish (Sebastes schlegelii) through liver transcriptome and metabolome analysis. Transcriptome results showed that liver genes associated with cell cycle and fatty acid synthesis were down-regulated, whereas those related to fatty acid decomposition were up-regulated in the experimental group (EG; starved for 72 days) compared to the control group (CG; feeding). Metabolomic results showed that there were significant differences in the levels of metabolites related to nucleotide metabolism and energy metabolism, such as purine metabolism, histidine metabolism and oxidative phosphorylation. Five fatty acids (C22:6n-3; C22:5n-3; C20:5n-3; C20:4n-3; C18:3n-6) were selected as possible biomarkers of starvation stress from the differential metabolites of metabolome. Subsequently, correlation between these differential genes of lipid metabolism and cell cycle and differential metabolites were analyzed, and observed that these five fatty acids were significantly correlated with the differential genes. These results provide new clues for understanding the role of fatty acid metabolism and cell cycle in fish under starvation stress. It also provides a reference for promoting the biomarker identification of starvation stress and stress tolerance breeding research.

Baicalin ameliorates high fat diet-induced nonalcoholic fatty liver disease in mice via adenosine monophosphate-activated protein kinase-mediated regulation of SREBP1/Nrf2/NF-κB signaling pathways.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease around the world, imposing severe threats on human health. Unfortunately, no clinically approved drugs are available for use as yet. Baicalin (BA) is reported to have hepatoprotective effects, and it is not clear whether BA can treat NAFLD and how. Here, a high-fat diet (HFD)-induced NAFLD mouse model was established to explore the protective roles and mechanisms of BA against HFD-induced NAFLD. Physiochemical results showed that BA exhibited significantly protective effects against HFD-induced NAFLD in mice. Liver transcriptomic analysis revealed that BA attenuated HFD-induced NAFLD via activating AMPK pathway, which was confirmed by the AMPK inhibitor Compound C. Additionally, the expression changes of AMPK downstream genes demonstrated that BA exerted ameliorative effects against NAFLD through AMPK-mediated inhibition of SREBP1 and NF-κB pathways, and activation of Nrf2 pathway. Taken together, our study reveals the protective roles of BA against HFD-caused NAFLD through AMPK-mediated modulation of SREBP1/Nrf2/NF-κB pathways, suggesting that BA has potential drug development implications. Most importantly, our study creates a paradigm through the combination of molecular biology and bioinformatics for further studies of action mechanisms of biomolecules combating diseases.

4-Methylumbelliferone Targets Revealed by Public Data Analysis and Liver Transcriptome Sequencing.

4-methylumbelliferone (4MU) is a well-known hyaluronic acid synthesis inhibitor and an approved drug for the treatment of cholestasis. In animal models, 4MU decreases inflammation, reduces fibrosis, and lowers body weight, serum cholesterol, and insulin resistance. It also inhibits tumor progression and metastasis. The broad spectrum of effects suggests multiple and yet unknown targets of 4MU. Aiming at 4MU target deconvolution, we have analyzed publicly available data bases, including: 1. Small molecule library Bio Assay screening (PubChemBioAssay); 2. GO pathway databases screening; 3. Protein Atlas Database. We also performed comparative liver transcriptome analysis of mice on normal diet and mice fed with 4MU for two weeks. Potential targets of 4MU public data base analysis fall into two big groups, enzymes and transcription factors (TFs), including 13 members of the nuclear receptor superfamily regulating lipid and carbohydrate metabolism. Transcriptome analysis revealed changes in the expression of genes involved in bile acid metabolism, gluconeogenesis, and immune response. It was found that 4MU feeding decreased the accumulation of the glycogen granules in the liver. Thus, 4MU has multiple targets and can regulate cell metabolism by modulating signaling via nuclear receptors.

Integrative analysis of transcriptome and lipidome reveals fructose pro-steatosis mechanism in goose fatty liver.

To further explore the fructose pro-steatosis mechanism, we performed an integrative analysis of liver transcriptome and lipidome as well as peripheral adipose tissues transcriptome analysis using samples collected from geese overfed with maize flour (control group) and geese overfed with maize flour supplemented with 10% fructose (treatment group). Overfeeding period of the treatment group was significantly shorter than that of the control group (p < 0.05). Dietary supplementation with 10% fructose induced more severe steatosis in goose liver. Compared with the control group, the treatment group had lower in ceramide levels (p < 0.05). The key differentially expressed genes (DEGs) (control group vs. treatment group) involved in liver fatty acid biosynthesis and steroid biosynthesis were downregulated. The conjoint analysis between DEGs and different lipids showed that fatty acid biosynthesis and steroid biosynthesis were the highest impact score pathways. In conclusion, fructose expedites goose liver lipid accumulation maximization during overfeeding.

Hepatocellular Carcinoma Mouse Model Induced by SV40 T Antigen Expression: Whole Liver Transcriptome Analysis with Time- and Diet-varying RNA Expression

Hepatocellular Carcinoma Mouse Model Induced by SV40 T Antigen Expression: Whole Liver Transcriptome Analysis with Time- and Diet-varying RNA Expression