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Real-time quantitative PCR analysis of mouse liver tissue and liver cells

ABSTRACT: Diets rich in fat is a major cause of common chronic liver diseases in worldwide and nutritional food has been widely used to counteract the metabolic disorders such as non-alcoholic fatty liver disease (NAFLD). The present study investigated the effects of oleuropein-enriched extract from Jasminum grandiflorum L. flowers (OLE-JGF), a medicinal plant that is also widely consumed as a beverage in China, in high fat diet (HFD) fed mice and oleic acid (OA)-treated AML-12 cells. Treatment of HFD-fed mice with 0.6% (w/w) OLE-JGF for 8 weeks significantly reduced the plasma levels of ALT, TC and LDL-C without changing the liver weight. Additionally, OLE-JGF administration significantly suppressed the mRNA expressions of the inflammatory mediators MCP-1 and CD68 in the liver of HFD-fed mice. Importantly, treatment with OLE-JGF significantly downregulated the key lipogenic enzymes (ACC and FAS) and their upstream transcription factor SREBP-1c in the liver. In the same time, mitochondrial DNA and UCP2 were upregulated along with increased expression of mitochondrial biogenic promoters including LKB1 and its downstream gene PGC-1α, Nrf2 and Tfam, but not changed AMPK in liver. In vitro, treatment of OLE for 24 h significantly increased the cell viability and decreased the TG level in OA-induced AML-12 cells. OLE significantly inhibited ACC mRNA expression and upregulated LKB1, PGC-1α and Tfam mRNA levels in OA-treated cells. In addition, OLE significantly increased the binding level of LKB1 to PGC-1α promoter in OA-induced cells. These findings indicate that OLE-JGF attenuates hepatocyte damage in HFD-fed mice and OA-induced liver cells, may be partly attributed to upregulation of LKB1-PGC-1α axis, which mediates hepatic lipogenesis and mitochondrial biogenesis. Our study provides a scientific basis for the benefits of J. grandiflorum flower as a supplement for met-abolic disease and potential use of OLE for the treatment of chronic liver diseases.

ORGANISM(S): Mus musculus Mus

PROVIDER: GSE202707 | GEO | 2022/05/14

REPOSITORIES: GEO

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Project description:PGC-1a is a transcriptional coactivator known to regulate a broad gene program of nutrient and mitochondrial metabolism. Many splice variants of this protein have been identified, but their functions were unknown. This experiment was designed to delineate the downstream targets of two different PGC-1alpha isoforms (PGC-1a1 and PGC-1a4) in hepatocytes, and to determine whether inflammatory signaling (via TNFR activation) modulated these targets Liver is exposed to constantly changing metabolic and inflammatory environments. It must quickly sense and adapt to metabolic need while balancing resources required to protect itself from harmful inflammatory molecules. PGC-1α is a transcriptional coactivator that mediates cellular adaptation to diverse stimuli including inflammation. PGC-1α has a protective role against inflammation in several organs, including brain, heart, kidney, muscle, and liver. However, it is not known how hepatic PGC-1α integrates extracellular signals to mitigate inflammatory outcomes. PGC-1α exists as multiple, alternatively spliced variants whose expression is differentially regulated by different gene promoters. In human liver, we found that inflammatory conditions preferentially activated the alternative versus proximal PPARGC1A promoter. Gene expression analysis performed in primary mouse hepatocytes identified many shared and isoform-specific roles for PGC-1α variants during acute inflammation. PGC-1α1 primarily impacted gene programs of nutrient and mitochondrial metabolism, while TNFα treatment revealed that PGC-1α4 uniquely influenced several pathways related to innate immunity and cell death. Gain- and loss-of-function models showed that PGC-1α4 specifically attenuated apoptosis in response to TNFα or LPS, in contrast to PGC-1α1, which reduced expression of a wide inflammatory gene network. We conclude that PGC-1α variants have distinct, yet complimentary roles in hepatic responses to inflammation, with PGC-1α4 being an important mitigator of apoptosis.

Project description:Title: Total Skeletal Muscle PGC-1 Deficiency Uncouples Mitochondrial Derangements from Fiber Type Determination and Insulin Sensitivity Abstract: Evidence is emerging that the PGC-1 coactivators serve a critical role in skeletal muscle metabolism, function, and disease. Mice with total PGC-1 deficiency in skeletal muscle (PGC-1α-/- βf/f/MLC-Cre mice) were generated and characterized. PGC-1α-/-βf/f/MLC-Cre mice exhibit a dramatic reduction in exercise performance compared to single PGC-1α- or PGC-1β-deficient mice and wild-type controls. The exercise phenotype of the PGC-1α-/-βf/f/MLC-Cre mice was associated with a marked diminution in muscle oxidative capacity and mitochondrial structural derangements consistent with fusion/fission and biogenic defects together with rapid depletion of muscle glycogen stores during exercise. Surprisingly, the skeletal muscle fiber type profile of the PGC-1α-/-βf/f/MLCCre mice was not significantly different than the wild-type mice. Moreover, insulin sensitivity and glucose tolerance were also not altered in the PGC-1α-/-βf/f/MLC-Cre mice. Taken together, we conclude that PGC-1 coactivators are necessary for the oxidative and mitochondrial programs of skeletal muscle but are dispensable for fundamental fiber type determination and insulin sensitivity. RNA from PGC-1alpha-/- beta f/f/Mlc1fcre was obtained and gene expression pattern compared with PGC-1alpha -/-, PGC-1beta f/f, and PGC-1beta f/f/Mlc1fCre controls. Results file descriptions: 1. GSE23365_skfloxAKO_PPexcl_genesup_GEO-8-16-2010: This table contains genes that were upregulated ≥2.0 fold in gastrocnemius muscle from PGC-1alpha-/- - mice, PGC-1beta f/f/Mlc1fCre mice and PGC-1alpha-/- - beta f/f/Mlc1fCre mice. All groups are normalized to PGC-1beta f/f mice and values are expressed as mean±SEM. The column “description’ contains the gene name, and the column “ID” contains Agilent probe names. 2. GSE23365_skfloxAKO_PPexcl_genesdown_GEO-8-16-2010 This table contains genes that were downregulated ≤0.7 fold in gastrocnemius muscle from PGC-1alpha-/- - mice, PGC-1beta f/f/Mlc1fCre mice and PGC-1alpha-/- - beta f/f/Mlc1fCre mice. All groups are normalized to PGC-1beta f/f mice and values are expressed as mean±SEM. The column “description’ contains the gene name, and the column “ID” contains Agilent probe names.

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Real-time quantitative PCR analysis of mouse liver tissue and liver cells

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