Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD

Fourman, Lindsay T; Billingsley, James M.; Agyapong, George; Sui, Shannan Ho; Feldpausch, Meghan N.; Purdy, Julia B.; Zheng, Isabel; Pan, Chelsea S; Corey, Kathleen E.; Torriani, Martin; Kleiner, David E.; Hadigan, Colleen; Stanley, Takara L.; Chung, Raymond T.; Grinspoon, Steven

doi:10.1172/jci.insight.140134

Cited by 16 publications

(12 citation statements)

References 47 publications

(65 reference statements)

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“…The clinical and molecular data from our study suggest that SARS-CoV-2-mediated liver injury is comparable to previously characterized hepatotropic viruses. For this reason, we compared publicly available datasets containing bulk RNA sequencing (RNA-seq) data from liver tissue samples from patients with hepatitis C virus (HCV) 23 , human immunodeficiency virus (HIV) 24 and hepatitis B virus (HBV) 25 via gene set enrichment analysis (GSEA) (Fig. 4a ).…”

Section: Mainmentioning

confidence: 99%

Molecular consequences of SARS-CoV-2 liver tropism

et al. 2022

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Extrapulmonary manifestations of COVID-19 have gained attention due to their links to clinical outcomes and their potential long-term sequelae1. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) displays tropism towards several organs, including the heart and kidney. Whether it also directly affects the liver has been debated2,3. Here we provide clinical, histopathological, molecular and bioinformatic evidence for the hepatic tropism of SARS-CoV-2. We find that liver injury, indicated by a high frequency of abnormal liver function tests, is a common clinical feature of COVID-19 in two independent cohorts of patients with COVID-19 requiring hospitalization. Using autopsy samples obtained from a third patient cohort, we provide multiple levels of evidence for SARS-CoV-2 liver tropism, including viral RNA detection in 69% of autopsy liver specimens, and successful isolation of infectious SARS-CoV-2 from liver tissue postmortem. Furthermore, we identify transcription-, proteomic- and transcription factor-based activity profiles in hepatic autopsy samples, revealing similarities to the signatures associated with multiple other viral infections of the human liver. Together, we provide a comprehensive multimodal analysis of SARS-CoV-2 liver tropism, which increases our understanding of the molecular consequences of severe COVID-19 and could be useful for the identification of organ-specific pharmacological targets.

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Section: Mainmentioning

confidence: 99%

Molecular consequences of SARS-CoV-2 liver tropism

et al. 2022

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“…Previous research has suggested that oxidative phosphorylation could reduce hepatic fibrosis. 51 The gene enrichment of MP3 oxidative phosphorylation hallmark gene set suggested the relative genes including cytochrome c oxidase subunit 5B ( COX5B) , cytochrome c oxidase subunit 7B ( COX7B) and ATP synthase membrane subunit e ( ATP5ME) upregulated (Fig. S6F ).…”

Section: Resultsmentioning

confidence: 99%

Multi-omics analysis of human tendon adhesion reveals that ACKR1-regulated macrophage migration is involved in regeneration

Zhang,

Xiao,

et al. 2024

Bone Res

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Tendon adhesion is a common complication after tendon injury with the development of accumulated fibrotic tissues without effective anti-fibrotic therapies, resulting in severe disability. Macrophages are widely recognized as a fibrotic trigger during peritendinous adhesion formation. However, different clusters of macrophages have various functions and receive multiple regulation, which are both still unknown. In our current study, multi-omics analysis including single-cell RNA sequencing and proteomics was performed on both human and mouse tendon adhesion tissue at different stages after tendon injury. The transcriptomes of over 74 000 human single cells were profiled. As results, we found that SPP1+ macrophages, RGCC+ endothelial cells, ACKR1+ endothelial cells and ADAM12+ fibroblasts participated in tendon adhesion formation. Interestingly, despite specific fibrotic clusters in tendon adhesion, FOLR2+ macrophages were identified as an antifibrotic cluster by in vitro experiments using human cells. Furthermore, ACKR1 was verified to regulate FOLR2+ macrophages migration at the injured peritendinous site by transplantation of bone marrow from Lysm-Cre;R26RtdTomato mice to lethally irradiated Ackr1−/− mice (Ackr1−/− chimeras; deficient in ACKR1) and control mice (WT chimeras). Compared with WT chimeras, the decline of FOLR2+ macrophages was also observed, indicating that ACKR1 was specifically involved in FOLR2+ macrophages migration. Taken together, our study not only characterized the fibrosis microenvironment landscape of tendon adhesion by multi-omics analysis, but also uncovered a novel antifibrotic cluster of macrophages and their origin. These results provide potential therapeutic targets against human tendon adhesion.

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“…GH increases lipolysis in adipose tissue, mobilizing FFA into systemic circulation [29] . GH also increases the beta-oxidation of FFA [30–32] , an effect expected to decrease hepatic lipid. Additionally, GH suppresses hepatic DNL [33–38] , a process that is an important contributor to stored hepatic lipid in NAFLD [39] .…”

Section: Effects Of Gh and Igf-1 In The Livermentioning

confidence: 99%

Growth hormone and nonalcoholic fatty liver disease

Ingrid

Stanley

2023

Immunometabolism

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Nonalcoholic fatty liver disease (NAFLD) is a prevalent cause of liver disease and metabolic comorbidities. Obesity is strongly associated with NAFLD and is also a state of relative deficiency of growth hormone (GH). Evidence supports a role of reduced GH and insulin-like growth factor-1 (IGF-1) in NAFLD pathogenesis. Physiological actions of GH in the liver include suppression of de novo lipogenesis (DNL) and promotion of lipid beta-oxidation, and GH also appears to have anti-inflammatory actions. Physiologic actions of IGF-1 include suppression of inflammatory and fibrogenic pathways important in the evolution from steatosis to steatohepatitis and fibrosis. Rodent models of impaired hepatic GH signaling show the development of steatosis, sometimes accompanied by inflammation, hepatocellular damage, and fibrosis, and these changes are ameliorated by treatment with GH and/or IGF-1. In humans, individuals with GH deficiency and GH resistance demonstrate an increased prevalence of NAFLD compared to controls, with improvement in hepatic lipid, steatohepatitis, and fibrosis following GH replacement. As a corollary, individuals with GH excess demonstrate lower hepatic lipid compared to controls along with increased hepatic lipid following treatment to normalize GH levels. Clinical trials demonstrate that augmentation of GH reduces hepatic lipid content in individuals with NAFLD and may also ameliorate steatohepatitis and fibrosis. Taken together, evidence supports an important role for perturbations in the GH/IGF-1 axis as one of the pathogenic mechanisms of NAFLD and suggests that further study is needed to assess whether augmentation of GH and/or IGF-1 may be a safe and effective therapeutic strategy for NAFLD.

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Effects of tesamorelin on hepatic transcriptomic signatures in HIV-associated NAFLD

Cited by 16 publications

References 47 publications

Molecular consequences of SARS-CoV-2 liver tropism

Molecular consequences of SARS-CoV-2 liver tropism

Multi-omics analysis of human tendon adhesion reveals that ACKR1-regulated macrophage migration is involved in regeneration

Growth hormone and nonalcoholic fatty liver disease

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