th9507 and Non-alcoholic-Fatty-Liver-Disease

Growth hormone (GH) and IGF-1 help regulate hepatic glucose and lipid metabolism, and reductions in these hormones may contribute to development of nonalcoholic fatty liver disease (NAFLD).. To assess relationships between hepatic expression of IGF1 and IGF-binding proteins (IGFBPs) and measures of glycemia and liver disease in adults with NAFLD. Secondarily to assess effects of GH-releasing hormone (GHRH) on circulating IGFBPs.. Analysis of data from a randomized clinical trial of GHRH.. Two US academic medical centers.. Participants were 61 men and women 18 to 70 years of age with HIV-infection, ≥5% hepatic fat fraction, including 39 with RNA-Seq data from liver biopsy.. Hepatic steatosis, inflammation, and fibrosis by histopathology and measures of glucose homeostasis.. Hepatic IGF1 mRNA was significantly lower in individuals with higher steatosis and NAFLD Activity Score (NAS) and was inversely related to glucose parameters, independent of circulating IGF-1. Among the IGFBPs, IGFBP2 and IGFBP4 were lower and IGFBP6 and IGFBP7 (also known as IGFBP-related protein 1) were higher with increasing steatosis. Hepatic IGFBP6 and IGFBP7 mRNA levels were positively associated with NAS. IGFBP7 mRNA increased with increasing fibrosis. Hepatic IGFBP1 mRNA was inversely associated with glycemia and insulin resistance, with opposite relationships present for IGFBP3 and IGFBP7. GHRH increased circulating IGFBP-1 and IGFBP-3, but decreased IGFBP-2 and IGFBP-6.. These data demonstrate novel relationships of IGF-1 and IGFBPs with NAFLD severity and glucose control, with divergent roles seen for different IGFBPs. Moreover, the data provide new information on the complex effects of GHRH on IGFBPs.

Topics: Adult; Blood Glucose; Double-Blind Method; Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Growth Hormone-Releasing Hormone; HIV; HIV Infections; Humans; Insulin-Like Growth Factor Binding Proteins; Insulin-Like Growth Factor I; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Severity of Illness Index

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.

Topics: Carcinoma, Hepatocellular; Female; Gene Expression; Growth Hormone; Growth Hormone-Releasing Hormone; Hepatitis; HIV Infections; Humans; Insulin-Like Growth Factor I; Liver; Liver Neoplasms; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Oxidative Phosphorylation; Placebos; Prognosis

Non-alcoholic fatty liver disease (NAFLD) is a substantial cause of comorbidity in people with HIV and there are no proven pharmacological treatments for the disease in this population. We assessed the effects of tesamorelin on liver fat and histology in people with HIV and NAFLD.. This randomised, double-blind, multicentre study with identical placebo as a comparator was done in a hospital and a medical research centre in the USA. People with HIV infection and a hepatic fat fraction (HFF) of 5% or more by proton magnetic resonance spectroscopy were eligible. Participants were randomly assigned (1:1) to receive either tesamorelin 2 mg once daily or placebo once daily for 12 months, followed by a 6-month open-label phase during which all participants received tesamorelin 2 mg daily. The randomisation list was prepared by the study statistician using a permuted block algorithm within each stratum with randomly varying block sizes. The primary endpoint was change in HFF between baseline and 12 months. The primary safety endpoint was glucose. Analysis was by intention to treat using all available data. This trial is registered with ClinicalTrials.gov, number NCT02196831.. 61 patients were enrolled between Aug 20, 2015, and Jan 16, 2019, of whom 30 received tesamorelin and 30 received placebo. Patients receiving tesamorelin had a greater reduction of HFF than did patients receiving placebo, with an absolute effect size of -4·1% (95% CI -7·6 to -0·7, p=0·018), corresponding to a -37% (95% CI -67 to -7, p=0·016) relative reduction from baseline. After 12 months, 35% of individuals receiving tesamorelin and 4% receiving placebo had a HFF of less than 5% (p=0·0069). Changes in fasting glucose and glycated haemoglobin were not different between groups at 12 months. Individuals in the tesamorelin group experienced more localised injection site complaints than those in the placebo group, though none were judged to be serious.. Tesamorelin might be beneficial in people with HIV and NAFLD. Further studies are needed to determine the long-term effects of tesamorelin on liver histology.. National Institutes of Health and National Institute of Allergy and Infectious Diseases.

Topics: Adult; Aged; Double-Blind Method; Female; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Liver; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Treatment Outcome; United States

NAFLD is a leading comorbidity in HIV with an exaggerated course compared to the general population. Tesamorelin has been demonstrated to reduce liver fat and prevent fibrosis progression in HIV-associated NAFLD. We further showed that tesamorelin downregulated hepatic gene sets involved in inflammation, tissue repair, and cell division. Nonetheless, effects of tesamorelin on individual plasma proteins pertaining to these pathways are not known. Leveraging our prior randomized-controlled trial and transcriptomic approach, we performed a focused assessment of 9 plasma proteins corresponding to top leading edge genes within differentially modulated gene sets. Tesamorelin led to significant reductions in vascular endothelial growth factor A (VEGFA, log

Topics: Adolescent; Adult; Aged; Blood Proteins; Double-Blind Method; Female; Growth Hormone-Releasing Hormone; Growth Substances; HIV Infections; Humans; Male; Middle Aged; Non-alcoholic Fatty Liver Disease; Placebos; Proteomics; Randomized Controlled Trials as Topic; Transcriptome; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A; Young Adult

Topics: Double-Blind Method; Growth Hormone-Releasing Hormone; HIV Infections; Humans; Liver; Non-alcoholic Fatty Liver Disease