Effects of Tesamorelin on Hepatic Transcriptomic Signatures in HIV-Associated NAFLD
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ABSTRACT:
PROVIDER: PRJNA630952 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11727600_1.fastq.gz | Fastqsanger.gz | |||
| SRR11727600_2.fastq.gz | Fastqsanger.gz | |||
| SRR11727601_1.fastq.gz | Fastqsanger.gz | |||
| SRR11727601_2.fastq.gz | Fastqsanger.gz | |||
| SRR11727602_1.fastq.gz | Fastqsanger.gz |
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Project description:Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity among people living with HIV with a more aggressive course than in the general population. In a recent randomized placebo-controlled trial, we demonstrated that the growth hormone-releasing hormone analogue tesamorelin reduced liver fat and prevented fibrosis progression in HIV-associated NAFLD over one year. In the current study, we leveraged paired liver biopsy specimens from this trial to identify hepatic gene pathways that are differentially modulated by tesamorelin versus placebo to gain key insights into the biological underpinnings of its clinical effects.
2020-09-08 | GSE150026 | GEO
Project description:Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity among people living with HIV that has a more aggressive course than NAFLD among the general population. In a recent randomized placebo-controlled trial, we demonstrated that the growth hormone-releasing hormone analog tesamorelin reduced liver fat and prevented fibrosis progression in HIV-associated NAFLD over 1 year. As such, tesamorelin is the first strategy that has shown to be effective against NAFLD among the population with HIV. The current study leveraged paired liver biopsy specimens from this trial to identify hepatic gene pathways that are differentially modulated by tesamorelin versus placebo. Using gene set enrichment analysis, we found that tesamorelin increased hepatic expression of hallmark gene sets involved in oxidative phosphorylation and decreased hepatic expression of gene sets contributing to inflammation, tissue repair, and cell division. Tesamorelin also reciprocally up- and downregulated curated gene sets associated with favorable and poor hepatocellular carcinoma prognosis, respectively. Notably, among tesamorelin-treated participants, these changes in hepatic expression correlated with improved fibrosis-related gene score. Our findings inform our knowledge of the biology of pulsatile growth hormone action and provide a mechanistic basis for the observed clinical effects of tesamorelin on the liver.
| S-EPMC7455119 | biostudies-literature
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
Project description:Obesity alters circulating levels of pituitary hormones that govern hepatic immune-metabolic homeostasis, and dysregulation of which leads to NAFLD. Here, using diet induced obese and IRE1PKO mice, we uncovered an blunted unfolded protein response (UPR) but elevated inflammatory signatures in pituitary glands of obese mice. Mechanistically, we demonstrated that the pituitary IRE1alpha-XBP1 UPR branch is essential for protecting against pituitary endocrine defects and NAFLD progression in obesity.
2024-04-30 | GSE263189 | GEO
Project description:Obesity alters circulating levels of pituitary hormones that govern hepatic immune-metabolic homeostasis, and dysregulation of which leads to NAFLD. Here, using diet induced obese mouse, we uncovered an blunted unfolded protein response (UPR) but elevated inflammatory signatures in pituitary glands of obese mice. Mechanistically, we demonstrated that the pituitary IRE1alpha-XBP1 UPR branch is essential for protecting against pituitary endocrine defects and NAFLD progression in obesity.
2024-04-30 | GSE263188 | GEO
Project description:Obesity alters circulating levels of pituitary hormones that govern hepatic immune-metabolic homeostasis, and dysregulation of which leads to NAFLD. Here, using diet induced obese mouse and IRE1PKO mice, we uncovered an blunted unfolded protein response (UPR) but elevated inflammatory signatures in pituitary glands of obese mice. Mechanistically, we demonstrated that the pituitary IRE1alpha-XBP1 UPR branch is essential for protecting against pituitary endocrine defects and NAFLD progression in obesity.
2024-04-30 | GSE263187 | GEO
Project description:The aim of this discovery case-control study was to identify patterns of differential expression of microRNAs in people living with HIV (PLWH) and assess their diagnostic value for non-alcoholic fatty liver disease (NALFD). Cases were defined as patients with severe NAFLD and controls as patients without NAFLD, characterized using the controlled attenuation parameter (CAP). Cases and controls were matched 1:1 for age, sex, body mass index, CD4+ lymphocyte count, active HCV infection, and ART regimen. Serum 2,083 simultaneous microRNA transcripts were analyzed using HTG technology and compared between cases and controls. Forty-five patients, 23 cases, and 22 controls were included in the study. In the analysis of the expression pattern of the 2,083 microRNAs, no differential expression patterns were found between both groups of patients included in the study. Analysis of the microRNA transcriptome profile of nonobese PLWH with severe NAFLD did not appear to differ from that of patients without NAFLD. Thus, microRNA might not serve as a proper biomarker for predicting severe NALFD in this population.
2023-05-03 | E-MTAB-12974 | biostudies-arrayexpress
Project description:To characterize gene expression changes in arachidonic acid metabolism pathway genes in the presense of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) mice administered were administered an atherogenic diet for a period of four weeks. Administration of the atherogenic diet resulted in significant enrichment of the arachidonic acid metabolism pathway by gene set enrichment analysis (GSEA). The core enrichment subset of genes was down-regulated in mice administered the atherogenic diet and the majority of the genes that were down-regulated were cytochrome P450s. A total of 4 wild-type mice were administered a standard diet (STD; control group) and 4 wild-type mice were administered a HFHC diet (HFHC).
2014-01-03 | E-GEOD-53381 | biostudies-arrayexpress
Project description:Protein post-translational modifications (PTMs) participate in important bioactive regulatory processes and therefore can help elucidate the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we investigate the involvement of PTMs in ketogenic diet (KD)-improved fatty liver by multi-omics and reveal a core target of lysine malonylation, acetyl-CoA carboxylase 1 (ACC1). ACC1 protein levels and Lys1523 malonylation are significantly decreased by KD. It is discovered that a malonylation-mimic mutant in ACC1 increases its enzyme activity and stability to promote hepatic steatosis, whereas the malonylation-null mutant upregulates the ubiquitination degradation of ACC1. A customized Lys1523ACC1 malonylation antibody confirms the increased malonylation of ACC1 in the NAFLD samples. Overall, the lysine malonylation of ACC1 is attenuated by KD in NAFLD and plays an important role in promoting hepatic steatosis. Malonylation is critical for ACC1 activity and stability, highlighting the anti-malonylation effect of ACC1 as a potential strategy for treating NAFLD.
2023-07-21 | PXD040481 | Pride
Project description:Cysteine dioxygenase type 1 (Cdo1) is a key enzyme for cysteine catabolism that is enriched in liver, whose role in NAFLD remains poorly understood. Here, we show that exercise induces the expression of hepatic Cdo1 via the cAMP/PKA/CREB signaling pathway. Hepatocyte-specific knockout of Cdo1 (Cdo1LKO) impairs the effect of exercise against NAFLD, whereas hepatocyte-specific overexpression of Cdo1 (Cdo1LTG) and exercise synergistically ameliorates NAFLD in male mice. Mechanistically, Cdo1 facilitates the binding between AMPK and kinase active Camkk2, which activates AMPK signaling. This promotes fatty acid oxidation and mitochondrial biogenesis in hepatocytes to attenuate hepatosteatosis. Therefore, by promoting hepatic Camkk2-AMPK signaling pathway, Cdo1 acts as an important downstream effector of exercise to combat against NAFLD
2023-08-07 | GSE239729 | GEO