Translatomics probes into the role of lycopene on improving hepatic steatosis induced by high-fat diet
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE178322 | GEO | 2021/06/17
REPOSITORIES: GEO
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Project description:Here, we found that microRNA-223 (miR-223) was highly elevated in hepatocytes after high fat diet (HFD) feeding in mice and in human nonalcoholic steatohepatitis (NASH) samples. Genetic deletion of the miR-223 induced a full spectrum of nonalcoholic fatty liver disease (NAFLD) in mice after long-term (up to one year) HFD feeding including NASH-related steatosis, inflammation, fibrosis and HCC. To better explore the mechanisms underlying the abnormalities observed in HFD-fed miR-223KO mice, we examined hepatic gene expression in 3-month-HFD-fed WT and miR-223KO mice by microarray analysis. Finally, we revealed that miR-223 plays a key role in controlling steatosis-to-NASH progression by inhibiting hepatic Cxcl10 and Taz expression.
2019-03-30 | GSE129080 | GEO
Project description:Abnormalities in hepatic lipid metabolism are believed to play a critical role in the etiology of nonalcoholic steatohepatitis (NASH). Monoacylglycerol acyltransferase (MGAT) enzymes convert monoacylglycerol to diacylglycerol, which is the penultimate step in one pathway for triacylglycerol (TAG) synthesis. Hepatic expression of Mogat1, which encodes an MGAT enzyme, is increased in the livers of mice with hepatic steatosis and knocking down Mogat1 improves insulin sensitivity, but whether increased MGAT activity plays a role in the etiology of NASH is unclear. To examine the effects of knocking down Mogat1 in the liver on the development of NASH, C57BL/6 mice were placed on a diet containing high levels of trans fatty acids, fructose, and cholesterol (HTF-C diet) or a low fat control diet for 4 weeks. Mice were then injected with antisense oligonucleotides (ASO) to knockdown Mogat1 or a scrambled ASO control for 12 weeks while remaining on diet. HTF-C diet caused glucose intolerance, hepatic steatosis, and induced hepatic gene expression markers of inflammation, macrophage infiltration, and stellate cell activation. Mogat1 ASO treatment, which suppressed Mogat1 expression in liver, attenuated weight gain, improved glucose tolerance, and decreased hepatic TAG content compared to control ASO-treated mice on HTF-C chow. However, Mogat1 ASO treatment did not reduce hepatic DAG, cholesterol, or free fatty acid content, improve histologic measures of liver injury, or reduce expression of markers of stellate cell activation, liver inflammation, and injury. In conclusion, inhibition of hepatic Mogat1 in HTF-C diet-fed mice improves glucose tolerance and hepatic TAG accumulation without attenuating liver inflammation and injury. Total RNA obtained from liver of 4 control vs. 4 Mogat1 ASO treated higf-fat diet (HFD) fed mice.
2014-11-05 | E-GEOD-60349 | biostudies-arrayexpress
Project description:Obesity is tightly associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms of obesity-induced fatty liver remain largely unknown.In order to identify genes that are potentially involved in dysfunctional hepatic lipid homeostasis in obesity, we performed a clustering analysis of Affymetrix arrays,which revealed that a number of mRNAs were dys-regulated in the livers of mice fed a high-fat diet (HFD), compared with mice fed a normal chow diet (ND). To identify genes that are potentially involved in dysfunctional hepatic lipid homeostasis in obesity, male C57BL/6 mice aged 8 weeks were fed a normal diet (ND) or high-fat-diet (HFD) containing 60 Kcal% of fat for 12 weeks. Then mice were sacrificed and total RNAs were isoloated from hepatic tissues. Affymetrix array hybridisation and scanning were performed using Mouse Genome 430 2.0 chips.Total RNA samples obtained from six mice per group (ND and HFD) and pooled by each of the two were used for microarray analysis.
2014-05-09 | E-GEOD-57425 | biostudies-arrayexpress
Project description:Translatomics probes into the role of lycopene on improving hepatic steatosis induced by high-fat diet
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Project description:Perfluorooctanesulfonic acid (PFOS) is a persistent, bio-accumulative pollutant that has been used for the last 60+ years in numerous industrial and commercial applications. In mice, PFOS administration is known to induce hepatomegaly and hepatic steatosis. The aim of the present study was to evaluate potential PFOS and diet interactions and explore the mechanism of PFOS induced liver lipid accumulation. Prior to PFOS administration, mice were fed either a standard chow diet (SD) or 60% kCal high fat diet (HFD) for 4 weeks to establish significant body weight increase. After 4 weeks of diet acclimation, the treatment groups received 0.0003% PFOS in diet for an additional 10 weeks. In addition, a subset of the mice fed HFD were switched to a SD (H-SD) to mimic weight-loss induced improvement of hepatic steatosis. A total of six treatment groups: i) SD, ii) HSD, iii) HFD (H), iv) SD +PFOS(SDP), v) H-SD +PFOS (HSDP), and vi) HFD +PFOS (HP) were included. PFOS and lipid concentrations were measured in both serum and liver. Relative liver mRNA expression was determined by targeted bead array and proteins were quantified using untargeted mass spectrometry. PFOS exposure increased liver weight, and in the HFD increased liver triglycerides and liver cholesterol content. Gene and protein expression in the liver demonstrated that PFOS exposure induced lipid utilization and xenobiotic metabolism pathways, and in a HFD, induced lipid synthesis. The data suggests that PFOS exposure acts on lipid utilization genes and exacerbates hepatic steatosis in mice fed a HFD.
2020-09-30 | PXD016161 | Pride
Project description:To identify molecular mechanism underlying the protection from diet-induced hepatic steatosis in AHNAK deficiency mice, we examined microarray analysis with liver sample from HFD-fed AHNAK KO and WT mice. Two-condition experiment, regular chow (CD) -fed WT vs. CD-fed AHNAK KO and High fat diet(HFD)-fed WT vs. HFD-fed AHNAK KO mice. Biological replicates: 3 control, One replicate per array.
2015-06-23 | E-GEOD-70119 | biostudies-arrayexpress
Project description:Adipose tissue dysfunction is closely associated with the development and progression of nonalcoholic fatty liver disease (NAFLD). Recent studies have implied an important role of prohibitin-1 (PHB1) in adipose tissue function. In the current study, we aimed to explore the function of adipocyte PHB1 in the development and progression of NAFLD. The PHB1 protein levels in adipose tissues were markedly decreased in mice fed a high-fat diet (HFD) compared to those fed a chow diet. To explore the function of adipocyte PHB1 in the progression of NAFLD, mice with adipocyte-specific (adipo) deletion of Phb1 (Phb1adipo-/- mice) were generated. Notably, Phb1adipo-/- mice did not develop obesity but displayed severe liver steatosis under HFD feeding. Compared to HFD-fed wild-type (WT) mice, HFD-fed Phb1adipo-/- mice displayed dramatically lower fat mass with significantly decreased levels of total adipose tissue inflammation, including macrophage and neutrophil number as well as the expression of inflammatory mediators. To our surprise, although liver steatosis in Phb1adipo-/- mice was much more severe, liver inflammation and fibrosis were similar to WT mice after HFD feeding. RNA sequencing analyses revealed that the interferon pathway was markedly suppressed while the bone morphogenetic protein 2 pathway was significantly up-regulated in the liver of HFD-fed Phb1adipo-/- mice compared with HFD-fed WT mice. Conclusion: HFD-fed Phb1adipo-/- mice display a subtype of the lean NAFLD phenotype with severe hepatic steatosis despite low adipose mass. This subtype of the lean NAFLD phenotype has similar inflammation and fibrosis as obese NAFLD in HFD-fed WT mice; this is partially due to reduced total adipose tissue inflammation and the hepatic interferon pathway.
2022-09-17 | GSE213355 | GEO
Project description:Individuals with hepatic steatosis often display several metabolic abnormalities including insulin resistance and muscle atrophy. Previously, we found that hepatic steatosis results in an altered hepatokine secretion profile, thereby inducing skeletal muscle insulin resistance via inter-organ crosstalk. In this study, we aimed to investigate whether the altered secretion profile in the state of hepatic steatosis also induces skeletal muscle atrophy via effects on muscle protein turnover. To investigate this, eight-week-old male C57BL/6J mice were fed a chow (4.5% fat) or a high-fat diet (HFD; 45% fat) for 12 weeks to induce hepatic steatosis, after which the livers were excised and cut into ~200 µm slices. Slices were cultured to collect secretion products (conditioned medium; CM). Differentiated L6-GLUT4myc myotubes were incubated with chow or HFD CM to measure glucose uptake. Differentiated C2C12 myotubes were incubated with chow or HFD CM to measure protein synthesis and breakdown, and gene expression via RNA sequencing. Furthermore, proteomics analysis was performed in chow and HFD CM. It was found that HFD CM caused insulin resistance in L6-GLUT4myc myotubes compared with chow CM, as indicated by a blunted insulin-stimulated increase in glucose uptake. Furthermore, protein breakdown was increased in C2C12 cells incubated with HFD CM, while there was no effect on protein synthesis. RNA profiling of C2C12 cells indicated that 197 genes were differentially expressed after incubation with HFD CM, compared with chow CM, and pathway analysis showed that pathways related to anatomical structure and function were enriched. Proteomic analysis of the CM showed that 32 proteins were differentially expressed in HFD CM compared with chow CM. Pathway enrichment analysis indicated that these proteins had important functions with respect to insulin-like Growth Factor transport and uptake, and affect post-translational processes, including protein folding, protein secretion and protein phosphorylation. In conclusion, the results of this study support the hypothesis that secretion products from the liver contribute to the development of muscle atrophy in individuals with hepatic steatosis.
2022-02-17 | PXD027332 | Pride
Project description:Long-term high fat feeding leads to hepatic steatosis, dyslipidemia, and a pro-inflammatory state. In a previous study, we observed this dysregulated metabolic phenotype when C57BL/6 mice were fed a high fat diet (HFD) for sixteen weeks. Additionally, a five-fold increase in liver gene expression of serum amyloid A-1 (SAA-1), an acute phase response protein that associates with high density lipoprotein (HDL), was observed. Inflammation induced changes composition may alter HDL functions, including anti-oxidant, anti-inflammatory and reverse cholesterol transport properties. Diet-induced onset and progression of HDL dysfunction is poorly understood. To examine the relationship between high fat diet and HDL dysfunction, we performed a short-term diet study. Four-week high fat feeding caused an increase in total plasma cholesterol compared with mice fed normal control diet (ND). No change in plasma triglycerides or development of hepatic steatosis was observed. These mice did however show evidence for increase in acute phase reactants, with a 3.25-fold increase in SAA-1 expression in liver. Heavy water labelling was used to determine the turnover rates of proteins associated with HDL. High fat diet resulted in increased fractional catabolic rate (HFD vs ND) of several acute phase response proteins involved ininnate immunity , including – Complement C3 (7.06 ± 0.99 vs 5.20 ± 0.56 %/h, p < 0.005), complement factor B (6.17 ± 0.59 vs 5.09 ± 0.87 %/h, p < 0.05), complement Factor H (4.16 ± 0.41 vs 3.56 ± 0.36 %/h, p < 0.05), and Complement factor I (3.50 ± 0.26 vs 2.75 ± 0.14 %/h, p < 0.005). Our findings suggest that early immune response-induced inflammatory remodeling of HDL precedes the diet-induced steatosis and dyslipidemia. Early HDL dysfunction reflected on impaired reverse cholesterol transport likely results in increase in plasma cholesterol in the absence of other lipid abnormalities.
2021-09-08 | PXD010272 | Pride
Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with increased risk in patients with metabolic syndrome. There are no FDA approved treatments, but farnesoid X receptor (FXR) agonists have shown promising results in clinical studies for NAFLD management. In addition to FXR, fibroblast growth factor receptor FGFR4 is a key mediator of hepatic bile acid synthesis. Using N-acetylgalactosamine-conjugated siRNA, we knocked down FGFR4 specifically in the liver of mice on chow or high-fat diet (HFD) and in mouse primary hepatocytes to determine the role of FGFR4 in metabolic processes and hepatic steatosis. Liver-specific FGFR4 silencing increased bile acid production and lowered serum cholesterol. Additionally, we found that HFD-induced liver steatosis and insulin resistance improved following FGFR4 knockdown. These improvements were associated with activation of the FXR-FGF15 axis in intestinal cells, but not in hepatocytes. We conclude that targeting FGFR4 in the liver to activate the intestinal FXR-FGF15 axis may be a promising strategy for the treatment of NAFLD and metabolic dysfunction.
2023-01-05 | GSE222171 | GEO