It is clear that insulin-like growth factor-1 (IGF1) is important in supporting growth and regulating metabolism. The IGF1 found in the circulation is primarily produced by the liver hepatocytes, but healthy mature hepatocytes do not express appreciable levels of the IGF1 receptor (IGF1R). Therefore, the metabolic actions of IGF1 are thought to be mediated via extra-hepatocyte actions. Given the structural and functional homology between IGF1/IGF1R and insulin receptor (INSR) signaling, and the fact that IGF1, IGF1R and INSR are expressed in most tissues of the body, it is difficult to separate out the tissue-specific contributions of IGF1/IGF1R in maintaining whole body metabolic function. To circumvent this problem, over the last 20 years, investigators have taken advantage of the Cre/loxP system to manipulate IGF1/IGF1R in a tissue-dependent, and more recently, an age-dependent fashion. These studies have revealed that IGF1/IGF1R can alter extra-hepatocyte function to regulate hormonal inputs to the liver and/or alter tissue-specific carbohydrate and lipid metabolism to alter nutrient flux to liver, where these actions are not mutually exclusive, but serve to integrate the function of all tissues to support the metabolic needs of the organism.
BackgroundType-2 diabetes mellitus (T2DM) is a major health problem with increasing incidence, which severely impacts cardiovascular disease. Because T2DM is associated with altered gene expression and aberrant splicing, we hypothesized that dysregulations in splicing machinery could precede, contribute to, and predict T2DM development.MethodsA cohort of patients with cardiovascular disease (CORDIOPREV study) and without T2DM at baseline (at the inclusion of the study) was used (n = 215). We determined the expression of selected splicing machinery components in fasting and 4 h-postprandial peripheral blood mononuclear cells (PBMCs, obtained at baseline) from all the patients who developed T2DM during 5-years of follow-up (n = 107 incident-T2DM cases) and 108 randomly selected non-T2DM patients (controls). Serum from incident-T2DM and control patients was used to analyze in vitro the modulation of splicing machinery expression in control PBMCs from an independent cohort of healthy subjects.FindingsExpression of key splicing machinery components (e.g. RNU2, RNU4 or RNU12) from fasting and 4 h-postprandial PBMCs of incident-T2DM patients was markedly altered compared to non-T2DM controls. Moreover, in vitro treatment of healthy individuals PBMCs with serum from incident-T2DM patients (compared to non-T2DM controls) reduced the expression of splicing machinery elements found down-regulated in incident-T2DM patients PBMCs. Finally, fasting/postprandial levels of several splicing machinery components in the PBMCs of CORDIOPREV patients were associated to higher risk of T2DM (Odds Ratio > 4) and could accurately predict (AUC > 0.85) T2DM development.InterpretationOur results reveal the existence of splicing machinery alterations that precede and predict T2DM development in patients with cardiovascular disease.FundISCIII, MINECO, CIBERObn.
Nonalcoholic fatty liver disease (NAFLD), which includes nonalcoholic steatohepatitis (NASH), is associated with reduced GH input/signaling, and GH therapy is effective in the reduction/resolution of NAFLD/NASH in selected patient populations. Our laboratory has focused on isolating the direct vs indirect effects of GH in preventing NAFLD/NASH. We reported that chow-fed, adult-onset, hepatocyte-specific, GH receptor knockdown (aHepGHRkd) mice rapidly (within 7 days) develop steatosis associated with increased hepatic de novo lipogenesis (DNL), independent of changes in systemic metabolic function. In this study, we report that 6 months after induction of aHepGHRkd early signs of NASH develop, which include hepatocyte ballooning, inflammation, signs of mild fibrosis, and elevated plasma alanine aminotransferase. These changes occur in the presence of enhanced systemic lipid utilization, without evidence of white adipose tissue lipolysis, indicating that the liver injury that develops after aHepGHRkd is due to hepatocyte-specific loss of GH signaling and not due to secondary defects in systemic metabolic function. Specifically, enhanced hepatic DNL is sustained with age in aHepGHRkd mice, associated with increased hepatic markers of lipid uptake/re-esterification. Because hepatic DNL is a hallmark of NAFLD/NASH, these studies suggest that enhancing hepatocyte GH signaling could represent an effective therapeutic target to reduce DNL and treat NASH.
A reduction in hepatocyte growth hormone (GH)-signaling promotes non-alcoholic fatty liver disease (NAFLD). However, debate remains as to the relative contribution of the direct effects of GH on hepatocyte function versus indirect effects, via alterations in insulin-like growth factor 1 (IGF1). To isolate the role of hepatocyte GH receptor (GHR) signaling, independent of changes in IGF1, mice with adult-onset, hepatocyte-specific GHR knockdown (aHepGHRkd) were treated with a vector expressing rat IGF1 targeted specifically to hepatocytes. Compared to GHR-intact mice, aHepGHRkd reduced circulating IGF1 and elevated GH. In male aHepGHRkd, the shift in IGF1/GH did not alter plasma glucose or non-esterified fatty acids (NEFA), but was associated with increased insulin, enhanced systemic lipid oxidation and reduced white adipose tissue (WAT) mass. Livers of male aHepGHRkd exhibited steatosis associated with increased de novo lipogenesis, hepatocyte ballooning and inflammation. In female aHepGHRkd, hepatic GHR protein levels were not detectable, but moderate levels of IGF1 were maintained, with minimal alterations in systemic metabolism and no evidence of steatosis. Reconstitution of hepatocyte IGF1 in male aHepGHRkd lowered GH and normalized insulin, whole body lipid utilization and WAT mass. However, IGF1 reconstitution did not reduce steatosis or eliminate liver injury. RNAseq analysis showed IGF1 reconstitution did not impact aHepGHRkd-induced changes in liver gene expression, despite changes in systemic metabolism. These results demonstrate the impact of aHepGHRkd is sexually dimorphic and the steatosis and liver injury observed in male aHepGHRkd mice is autonomous of IGF1, suggesting GH acts directly on the adult hepatocyte to control NAFLD progression.
ObjectivesTo characterise splicing machinery (SM) alterations in leucocytes of patients with rheumatoid arthritis (RA), and to assess its influence on their clinical profile and therapeutic response.MethodsLeucocyte subtypes from 129 patients with RA and 29 healthy donors (HD) were purified, and 45 selected SM elements (SME) were evaluated by quantitative PCR-array based on microfluidic technology (Fluidigm). Modulation by anti-tumour necrosis factor (TNF) therapy and underlying regulatory mechanisms were assessed.ResultsAn altered expression of several SME was found in RA leucocytes. Eight elements (SNRNP70, SNRNP200, U2AF2, RNU4ATAC, RBM3, RBM17, KHDRBS1 and SRSF10) were equally altered in all leucocytes subtypes. Logistic regressions revealed that this signature might: discriminate RA and HD, and anti-citrullinated protein antibodies (ACPAs) positivity; classify high-disease activity (disease activity score-28 (DAS28) >5.1); recognise radiological involvement; and identify patients showing atheroma plaques. Furthermore, this signature was altered in RA synovial fluid and ankle joints of K/BxN-arthritic mice. An available RNA-seq data set enabled to validate data and identified distinctive splicing events and splicing variants among patients with RA expressing high and low SME levels. 3 and 6 months anti-TNF therapy reversed their expression in parallel to the reduction of the inflammatory profile. In vitro, ACPAs modulated SME, at least partially, by Fc Receptor (FcR)-dependent mechanisms. Key inflammatory cytokines further altered SME. Lastly, induced SNRNP70-overexpression and KHDRBS1-overexpression reversed inflammation in lymphocytes, NETosis in neutrophils and adhesion in RA monocytes and influenced activity of RA synovial fibroblasts.ConclusionsOverall, we have characterised for the first time a signature comprising eight dysregulated SME in RA leucocytes from both peripheral blood and synovial fluid, linked to disease pathophysiology, modulated by ACPAs and reversed by anti-TNF therapy.
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