Dietary amino acid source elicits sex-specific metabolic response to diet-induced NAFLD in murine model.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE234591 | GEO | 2024/01/01
REPOSITORIES: GEO
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Project description:Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. There is growing evidence that dysbiosis of the intestinal microbiota and disruption of microbiota-host interactions contribute to the pathology of NAFLD. We previously demonstrated that gut microbiota derived tryptophan metabolite indole-3-acetate (I3A) was decreased in both cecum and liver of high-fat diet-fed mice and attenuated the expression of inflammatory cytokines in macrophages and TNF-a and fatty acid induced inflammatory responses in an aryl-hydrocarbon receptor (AhR) dependent manner in hepatocytes. In this study, we investigated the effect of orally administered I3A in a mouse model of diet induced NAFLD. Western diet (WD)-fed mice given sugar water (SW) with I3A showed dramatically decreased serum ALT, hepatic TG, liver steatosis, hepatocyte ballooning, lobular inflammation, and hepatic production of inflammatory cytokines, compared to WD-fed mice given only SW. Metagenomic analysis show that I3A administration did not significantly modify the intestinal microbiome, suggesting that I3A’s beneficial effects likely reflect the metabolite’s direct actions on the liver. Administration of I3A partially reversed WD induced alterations of liver metabolome and proteome, notably, decreasing expression of several enzymes in hepatic lipogenesis and β- oxidation. Mechanistically, we also show that AMP-activated protein kinase (AMPK) mediates the anti-inflammatory effects of I3A in macrophages. The potency of I3A in alleviating liver steatosis and inflammation clearly demonstrates its potential as a therapeutic modality for preventing the progression of steatosis to NASH.
2024-02-23 | PXD046255 | Pride
Project description:We used microarray to determine the differences in hepatic gene expression for diet-induced obese Sprague-Dawley rats consuming different dietary proteins. Proteins of interest included skim milk powder (dairy), casein, and the branched-chain amino acid, leucine. The primary aims of this study were: (i) to compare the effects of diets with protein derived from casein, casein supplemented with leucine, and complete dairy on body composition and insulin sensitivity; and (ii) to determine if there is a synergistic effect of dietary Ca and protein source on body composition and insulin sensitivity. Secondarily, we used microarray analysis to examine the effect of casein, leucine, or complete dairy containing diets on the expression of hepatic genes related to lipid and glucose metabolism.
2010-08-12 | GSE23559 | GEO
Project description:We used microarray to determine the differences in hepatic gene expression for diet-induced obese Sprague-Dawley rats consuming different dietary proteins. Proteins of interest included skim milk powder (dairy), casein, and the branched-chain amino acid, leucine. The primary aims of this study were: (i) to compare the effects of diets with protein derived from casein, casein supplemented with leucine, and complete dairy on body composition and insulin sensitivity; and (ii) to determine if there is a synergistic effect of dietary Ca and protein source on body composition and insulin sensitivity. Secondarily, we used microarray analysis to examine the effect of casein, leucine, or complete dairy containing diets on the expression of hepatic genes related to lipid and glucose metabolism. Diet induced obese rats consumed ad libitum, a high fat, high sucrose diet for 8 weeks (n=4). All diets had an energy density of 4.6 kcal/gram and provided 10% of total energy from protein [casein, complete dairy (skim milk powder), or leucine-supplemented casein (7.1% from casein plus 2.9% from leucine)]. The casein treatment was the control diet.
2010-08-12 | E-GEOD-23559 | biostudies-arrayexpress
Project description:Ingestion of a diet with a restricted Methionine (MR) content results in robust activation of hepatic stress pathways regulated by PERK, ATF4, and Nfe2l2. In addition, genes regulating hepatic lipogenesis are downregulated. So far, data were obtained using a mix of elemental amino acids as the dietary protein source, which was replaced in this experiment with casein. To reduce methionine content, casein was oxidized and methionine was added back to a concentration similar to the diets using elemental amino acids as protein source. Results show that mice reduce body weight and adiposity on MR containing oxidized casein similar to MR containing elemental amino acids. Similarly, energy expenditure, as well as food and water intake were increased. The RNAseq experiment was conducted to compare the effect of MR using these two protein sources on the hepatic transcriptome.
2021-06-09 | GSE162918 | GEO
Project description:We used microarray to determine the differences in hepatic gene expression for diet-induced obese Sprague-Dawley rats consuming different dietary proteins. Proteins of interest included skim milk powder (dairy), casein, and the branched-chain amino acid, leucine. The primary aims of this study were: (i) to compare the effects of diets with protein derived from casein, casein supplemented with leucine, and complete dairy on body composition and insulin sensitivity; and (ii) to determine if there is a synergistic effect of dietary Ca and protein source on body composition and insulin sensitivity. Secondarily, we used microarray analysis to examine the effect of casein, leucine, or complete dairy containing diets on the expression of gastrocnemius muscle genes related to lipid and glucose metabolism.
2011-10-22 | GSE33144 | GEO
Project description:Background & Aims: Overnutrition is one of the major causes of non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH). Besides the quantity of consumed calories, distinct dietary components are increasingly recognized as important contributor to the pathogenesis of NASH. We aimed to develop and characterize a hitherto missing murine model which resembles both the pathology and nutritional situation of NASH-patients in Western societies. Methods: We developed a NASH-inducing diet (ND) enriched with sucrose, cholesterol and a high concentration of fats rich in saturated fatty acids in a composition which mimics Western food. C57Bl6/N mice were fed with the ND or control chow for 12 weeks. Biochemical, real-time polymerase chain reaction, Western Blot and immunohistochemical analyses were performed to characterize systemic and hepatic changes induced by ND-feeding. Immunohistochemistry was used to assess c-Jun levels and activation in 110 human NAFLD and control liver specimens applying tissue micro array technology. Results: ND-fed mice showed significant body weight gain, impaired glucose tolerance, elevated fasting blood glucose levels as well as decreased adiponectin and increased leptin serum levels compared to control mice. In the liver, ND-feeding led to marked steatosis, enhanced cholesterol levels, distinct signs of oxidative stress, hepatocellular damage, inflammation, activation of hepatic stellate cells, and beginning fibrosis. Transcriptome-wide hepatic gene expression analysis comparing ND-fed mice and control mice indicated main alterations in lipid metabolism and inflammatory processes. Search for over-represented transcription factor target sites among the differentially expressed genes identified AP-1 as the most likely factor to cause the transcriptional changes in ND-livers. Combining differentially expressed gene and protein-protein interaction network analysis identified c-Jun (a component of the AP-1 complex) as hub in the largest connected deregulated sub-network in ND-livers. In accordance, ND-livers revealed c-Jun-phosphorylation and nuclear translocation. Moreover, hepatic c-Jun RNA and protein expression was enhanced in ND-fed compared to control mice. Also NAFLD-patients showed enhanced hepatic c-Jun levels, which correlated with inflammation, and notably, with the degree of hepatic steatosis. Conclusions: The new dietary mouse-model shows important pathological changes also found in human NASH and indicates c-jun/AP-1 activation as critical regulator of hepatic alterations. Abundance of c-jun in NAFLD likely facilitates development and progression of NASH, and thus, c-jun appears as attractive prognostic and therapeutic target of NAFLD progression. 14-weeks old male C57BL/6N mice were fed with either regular diet or a newly designed NASH-inducing diet for 12 weeks. Hepatic gene expression levels were measured thereafter.
2014-02-01 | E-GEOD-52748 | biostudies-arrayexpress
Project description:We used microarray to determine the differences in hepatic gene expression for diet-induced obese Sprague-Dawley rats consuming different dietary proteins. Proteins of interest included skim milk powder (dairy), casein, and the branched-chain amino acid, leucine. The primary aims of this study were: (i) to compare the effects of diets with protein derived from casein, casein supplemented with leucine, and complete dairy on body composition and insulin sensitivity; and (ii) to determine if there is a synergistic effect of dietary Ca and protein source on body composition and insulin sensitivity. Secondarily, we used microarray analysis to examine the effect of casein, leucine, or complete dairy containing diets on the expression of gastrocnemius muscle genes related to lipid and glucose metabolism. Diet induced obese rats consumed ad libitum, a high fat, high sucrose diet for 8 weeks (n=4). All diets had an energy density of 4.6 kcal/gram and provided 10% of total energy from protein [casein, complete dairy (skim milk powder), or leucine-supplemented casein (7.1% from casein plus 2.9% from leucine)]. The casein treatment was the control diet.
2011-10-21 | E-GEOD-33144 | biostudies-arrayexpress
Project description:Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease (CVD). Liver is the major source of the circulatory proteins and alterations in plasma proteome have been implicated in atherosclerosis. We used a recently developed 2H2O-metabolic labeling method in combination with the label-free quantification to evaluate the effect of a Western diet (WD) on the dynamics of plasma proteins in LDL receptor-deficient (LDLR-/-) mice, a model of NAFLD and atherosclerosis. There were no significant changes in the expression level of total proteins due to the WD with a bulk protein mean half-life of 18.0±15.1 hours in control and 16.7±11.1 hours in WD groups. WD led to pro-inflammatory distribution of circulatory proteins analyzed in apoB-depleted plasma attributed to their increased production. The fractional catabolic rates of fast-turnover proteins with stress-response, lipid metabolism and transport functions were significantly increased with WD (P<0.05). The pathway analyses revealed that alterations in plasma proteome dynamics were related to the suppression of hepatic PPARα, which was confirmed based on reduced gene and protein expression of PPARα on WD. These changes were associated with ~4 fold increase (P<0.0001) in pro-inflammatory property of apoB-depleted plasma. In conclusion, the proteome dynamics method reveals pro-inflammatory remodeling of plasma proteome relevant to liver disease. As in vivo metrics of liver function, this approach can be used to test therapies in NAFLD and other diseases
2016-06-06 | PXD004270 | Pride
Project description:Dietary Methionine restriction (MR) has been demonstrated to induce a set of hepatic responses, including activation of hepatic stress response and suppression of hepatic lipogenesis. In the current study, we used two different protein sources to achieve MR. Casein was used in normal protein (NP, 20% casein) and low protein (LP, 5% casein) diet. Soy protein was used in 20Soy (20% soy), 20Soy+SAA (20% soy, Met and Cys was added back to match their concentration in NP diet), and 10Soy (11.5% soy, the Met concentration matches LP diet). Results show that mice that were fed LP and 10Soy diet have lower body weight and adiposity and increased food and water intake, energy expenditure, and serum FGF21 levels compared to their relative controls. The RNAseq experiment was conducted to compare the effect of MR using these two protein sources on the hepatic transcriptome.
2021-09-01 | GSE168132 | GEO
Project description:Nonalcoholic fatty liver disease (NAFLD) is associated with hepatic mitochondrial dysfunction characterized by reduced ATP synthesis. We applied the 2H2O-metabolic labeling approach to test the hypothesis that the reduced stability of oxidative phosphorylation proteins contributes to mitochondrial dysfunction in a diet-induced mouse model of NAFLD. A high fat diet containing cholesterol (a so-called Western diet (WD)) led to hepatic oxidative stress, steatosis, inflammation and mild fibrosis, all markers of NAFLD, in LDLR-/- mice. In addition, compared to controls, livers from NAFLD mice had reduced citrate synthase activity and ATP content, suggesting reduced mitochondrial oxidative capacity. Proteome dynamics analysis revealed that mitochondrial dysfunction is associated with reduced average half-lives of mitochondrial proteins in NAFLD mice (5.41±0.46 vs. 5.15±0.49 day, P<0.05). In particular, the WD reduced stability of oxidative phosphorylation subunits, including cytochrome c oxidase subunit 4 isoform 1 of complex III (5.9 ± 0.1 vs 3.4 ± 0.8 day), ATP synthase subunit α (6.3±0.4 vs. 5.5±0.4 day) and ATP synthase F(0) complex subunit B1 of complex V (8.5±0.6 vs. 6.5±0.2 day) (P<0.05). These changes were associated with impaired complex III and F0F1-ATP synthase activities, suggesting that increased degradation of mitochondrial proteins contributed to hepatic mitochondrial dysfunction in NAFLD mice. Autophagy, but not proteasomal degradation, contributed to increased clearance of hepatic mitochondrial proteins in NAFLD mice. In conclusion, the proteome dynamics approach suggests that alterations in mitochondrial proteome dynamics is involved in hepatic mitochondrial dysfunction in NAFLD.
2018-11-21 | PXD008766 | Pride