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Kerstin Jahn-Hofmann

Bio: Kerstin Jahn-Hofmann is an academic researcher. The author has contributed to research in topics: Fatty liver & Lipid metabolism. The author has an hindex of 6, co-authored 14 publications receiving 96 citations.

Papers
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Journal ArticleDOI
01 Mar 2019-Diabetes
TL;DR: Upon NNMT deletion or knockdown in males and females fed different obesity-inducing diets, sex- and diet-specific differences in body composition, weight, and glucose tolerance are observed and estimates of IS are observed.
Abstract: Antisense oligonucleotide knockdown (ASO-KD) of nicotinamide N-methyltransferase (NNMT) in high-fat diet (HFD)-fed mice has been reported to reduce weight gain and plasma insulin levels and to improve glucose tolerance. Using NNMT-ASO-KD or NNMT knockout mice (NNMT-/-), we tested the hypothesis that Nnmt deletion protects against diet-induced obesity and its metabolic consequences in males and females on obesity-inducing diets. We also examined samples from a human weight reduction (WR) study for adipose NNMT (aNNMT) expression and plasma 1-methylnicotinamide (MNAM) levels. In Western diet (WD)-fed female mice, NNMT-ASO-KD reduced body weight, fat mass, and insulin level and improved glucose tolerance. Although NNMT-/- mice fed a standard diet had no obvious phenotype, NNMT-/- males fed an HFD showed strongly improved insulin sensitivity (IS). Furthermore, NNMT-/- females fed a WD showed reduced weight gain, less fat, and lower insulin levels. However, no improved glucose tolerance was observed in NNMT-/- mice. Although NNMT expression in human fat biopsy samples increased during WR, corresponding plasma MNAM levels significantly declined, suggesting that other mechanisms besides aNNMT expression modulate circulating MNAM levels during WR. In summary, upon NNMT deletion or knockdown in males and females fed different obesity-inducing diets, we observed sex- and diet-specific differences in body composition, weight, and glucose tolerance and estimates of IS.

39 citations

Journal ArticleDOI
TL;DR: It is shown that inducible mINDY inhibition improved hepatic insulin sensitivity and prevented diet-induced non-alcoholic fatty liver disease in adult C57BL6/J mice and did not depend on changes of body weight or body composition.
Abstract: Objective Non-alcoholic fatty liver disease is a world-wide health concern and risk factor for cardio-metabolic diseases. Citrate uptake modifies intracellular hepatic energy metabolism and is controlled by the conserved sodium-dicarboxylate cotransporter solute carrier family 13 member 5 (SLC13A5, mammalian homolog of INDY: mINDY). In Drosophila melanogast er and Caenorhabditis elegans INDY reduction decreased whole-body lipid accumulation. Genetic deletion of Slc13a5 in mice protected from diet-induced adiposity and insulin resistance. We hypothesized that inducible hepatic mINDY inhibition should prevent the development of fatty liver and hepatic insulin resistance. Methods Adult C57BL/6J mice were fed a Western diet (60% kcal from fat, 21% kcal from carbohydrate) ad libitum. Knockdown of mINDY was induced by weekly injection of a chemically modified, liver-selective siRNA for 8 weeks. Mice were metabolically characterized and the effect of mINDY suppression on glucose tolerance as well as insulin sensitivity was assessed with an ipGTT and a hyperinsulinemic-euglycemic clamp. Hepatic lipid accumulation was determined by biochemical measurements and histochemistry. Results Within the 8 week intervention, hepatic mINDY expression was suppressed by a liver-selective siRNA by over 60%. mINDY knockdown improved hepatic insulin sensitivity (i.e. insulin-induced suppression of endogenous glucose production) of C57BL/6J mice in the hyperinsulinemic-euglycemic clamp. Moreover, the siRNA-mediated mINDY inhibition prevented neutral lipid storage and triglyceride accumulation in the liver, while we found no effect on body weight. Conclusions We show that inducible mINDY inhibition improved hepatic insulin sensitivity and prevented diet-induced non-alcoholic fatty liver disease in adult C57BL6/J mice. These effects did not depend on changes of body weight or body composition.

36 citations

Journal ArticleDOI
23 Jul 2019
TL;DR: Hepatocyte‐targeted siTAZ is potentially a novel and clinically feasible treatment for NASH and partially reversed hepatic inflammation, injury, and fibrosis.
Abstract: Nonalcoholic steatohepatitis (NASH) is emerging as a major public health issue and is associated with significant liver-related morbidity and mortality. At present, there are no approved drug therapies for NASH. The transcriptional coactivator with PDZ-binding motif (TAZ; encoded by WW domain-containing transcription regulator 1 [WWTR1]) is up-regulated in hepatocytes in NASH liver from humans and has been shown to causally promote inflammation and fibrosis in mouse models of NASH. As a preclinical test of targeting hepatocyte TAZ to treat NASH, we injected stabilized TAZ small interfering RNA (siRNA) bearing the hepatocyte-specific ligand N-acetylgalactosamine (GalNAc-siTAZ) into mice with dietary-induced NASH. As a preventative regimen, GalNAc-siTAZ inhibited inflammation, hepatocellular injury, and the expression of profibrogenic mediators, accompanied by decreased progression from steatosis to NASH. When administered to mice with established NASH, GalNAc-siTAZ partially reversed hepatic inflammation, injury, and fibrosis. Conclusion: Hepatocyte-targeted siTAZ is potentially a novel and clinically feasible treatment for NASH.

34 citations

Journal ArticleDOI
TL;DR: Significant therapeutic benefit of β-catenin knock-down was demonstrated in established HCC tumor xenografts using doxycycline-inducible shRNA system and fundamental importance of aberrant β-catsin signaling in the maintenance of oncogenic phenotype in HCC is highlighted.
Abstract: Hepatocellular carcinoma (HCC) represents a serious public health challenge with few therapeutic options available to cancer patientsWnt/β-catenin pathway is thought to play a significant role in HCC pathogenesis In this study, we confirmed high frequency of CTNNB1 (β-catenin) mutations in two independent cohorts of HCC patients and demonstrated significant upregulation of β-catenin protein in the overwhelming majority of HCC patient samples, patient-derived xenografts (PDX) and established cell lines Using genetic tools validated for target specificity through phenotypic rescue experiments, we went on to investigate oncogenic dependency on β-catenin in an extensive collection of human HCC cells lines Our results demonstrate that dependency on β-catenin generally tracks with its activation status HCC cell lines that harbored activating mutations in CTNNB1 or displayed elevated levels of non-phosphorylated (active) β-catenin were significantly more sensitive to β-catenin siRNA treatment than cell lines with wild-type CTNNB1 and lower active β-catenin Finally, significant therapeutic benefit of β-catenin knock-down was demonstrated in established HCC tumor xenografts using doxycycline-inducible shRNA system β-catenin downregulation and tumor growth inhibition was associated with reduction in AXIN2, direct transcriptional target of β-catenin, and decreased cancer cell proliferation as measured by Ki67 staining Taken together, our data highlight fundamental importance of aberrant β-catenin signaling in the maintenance of oncogenic phenotype in HCC

17 citations

Journal ArticleDOI
TL;DR: Comprehensive data validating the concept and utility of treatment with synthetic RIG-I agonist ppp-RNA for the therapy of human cancer is presented, with melanoma as potential entry indication amenable to intratumoral treatment.
Abstract: The pattern recognition receptor RIG-I plays an important role in the recognition of nonself RNA and antiviral immunity. RIG-I's natural ligand, triphosphate RNA (ppp-RNA), is proposed to be a valuable addition to the growing arsenal of cancer immunotherapy treatment options. In this study, we present comprehensive data validating the concept and utility of treatment with synthetic RIG-I agonist ppp-RNA for the therapy of human cancer, with melanoma as potential entry indication amenable to intratumoral treatment. Using mRNA expression data of human tumors, we demonstrate that RIG-I expression is closely correlated to cellular and cytokine immune activation in a wide variety of tumor types. Furthermore, we confirm susceptibility of cancer cells to ppp-RNA treatment in different cellular models of human melanoma, revealing unexpected heterogeneity between cell lines in their susceptibility to RNA agonist features, including sequence, secondary structures, and presence of triphosphate. Cellular responses to RNA treatment (induction of type I IFN, FasR, MHC-I, and cytotoxicity) were demonstrated to be RIG-I dependent using KO cells. Following ppp-RNA treatment of a mouse melanoma model, we observed significant local and systemic antitumor effects and survival benefits. These were associated with type I IFN response, tumor cell apoptosis, and innate and adaptive immune cell activation. For the first time, we demonstrate systemic presence of tumor antigen-specific CTLs following treatment with RIG-I agonists. Despite potential challenges in the generation and formulation of potent RIG-I agonists, ppp-RNA or analogues thereof have the potential to play an important role for cancer treatment in the next wave of immunotherapy.

13 citations


Cited by
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TL;DR: In this article, the authors show that egfl7 mutants do not show any obvious phenotypes while animals injected with egfl 7 morpholino (morphants) exhibit severe vascular defects, indicating that the activation of a compensatory network to buffer against deleterious mutations was not observed after translational or transcriptional knockdown.
Abstract: Cells sense their environment and adapt to it by fine-tuning their transcriptome. Wired into this network of gene expression control are mechanisms to compensate for gene dosage. The increasing use of reverse genetics in zebrafish, and other model systems, has revealed profound differences between the phenotypes caused by genetic mutations and those caused by gene knockdowns at many loci, an observation previously reported in mouse and Arabidopsis. To identify the reasons underlying the phenotypic differences between mutants and knockdowns, we generated mutations in zebrafish egfl7, an endothelial extracellular matrix gene of therapeutic interest, as well as in vegfaa. Here we show that egfl7 mutants do not show any obvious phenotypes while animals injected with egfl7 morpholino (morphants) exhibit severe vascular defects. We further observe that egfl7 mutants are less sensitive than their wild-type siblings to Egfl7 knockdown, arguing against residual protein function in the mutants or significant off-target effects of the morpholinos when used at a moderate dose. Comparing egfl7 mutant and morphant proteomes and transcriptomes, we identify a set of proteins and genes that are upregulated in mutants but not in morphants. Among them are extracellular matrix genes that can rescue egfl7 morphants, indicating that they could be compensating for the loss of Egfl7 function in the phenotypically wild-type egfl7 mutants. Moreover, egfl7 CRISPR interference, which obstructs transcript elongation and causes severe vascular defects, does not cause the upregulation of these genes. Similarly, vegfaa mutants but not morphants show an upregulation of vegfab. Taken together, these data reveal the activation of a compensatory network to buffer against deleterious mutations, which was not observed after translational or transcriptional knockdown.

774 citations

Journal ArticleDOI
TL;DR: How members of the RLR family are regulated is explained and the importance of the RLRs in viral infection, autoimmunity and cancer is reflected on.
Abstract: Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are key sensors of virus infection, mediating the transcriptional induction of type I interferons and other genes that collectively establish an antiviral host response. Recent studies have revealed that both viral and host-derived RNAs can trigger RLR activation; this can lead to an effective antiviral response but also immunopathology if RLR activities are uncontrolled. In this Review, we discuss recent advances in our understanding of the types of RNA sensed by RLRs in the contexts of viral infection, malignancies and autoimmune diseases. We further describe how the activity of RLRs is controlled by host regulatory mechanisms, including RLR-interacting proteins, post-translational modifications and non-coding RNAs. Finally, we discuss key outstanding questions in the RLR field, including how our knowledge of RLR biology could be translated into new therapeutics.

636 citations

Journal ArticleDOI
TL;DR: How interactions between different liver cells culminate in fibrosis development in NASH are reviewed, focusing on triggers and consequences of hepatocyte–macrophage–hepatic stellate cell (HSC) crosstalk, and options to therapeutically interrupt this profibrogenic hepatocyte-macrophages-HSC network in NASh are summarized.

257 citations

Journal ArticleDOI
TL;DR: A review of the use of this delivery system for small interfering RNAs (siRNAs) and antisense molecules that cause downregulation of target mRNA and protein for therapeutic oligonucleotide intervention focuses on GalNAc.

136 citations