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Hergo Holzhütter

About Hergo Holzhütter:
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SEEK ID: https://seek.lisym.org/people/54

Location:  Germany

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LiSyM network

This comprises the whole LiSyM network

Programme: LiSyM: Liver Systems Medicine

Public web page: http://www.lisym.org

Start date: 1st Jan 2016

LiSyM-Krebs Partnering

This generic project is intended to be a forum for all LiSyM partner and external stakeholders interested in participating in the BMBF initiative LiSyM-Krebs.

Programme: LiSyM-Krebs

Public web page: https://www.ptj.de/projektfoerderung/gesundheitsforschung/lisym-krebs

LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi)

Disorders of the liver show up through changes in blood tests. These blood tests indicate markers for events taking place in the liver. Usually studies of liver tissue cannot be performed: as liver samples would need to be obtained through a liver biopsy, and this procedure is not without risk, therefore these samples are usually unavailable. Complex metabolism models based on existing and new scientific data can simulate changes in the liver caused by disease. They often reveal unknown relationships
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Programme: LiSyM: Liver Systems Medicine

Public web page: http://www.lisym.org/our-work/pillar-research/the-liver-is-very-patient

Start date: 1st Jan 2016

LiSyM Scientific Leadership Team (LiSyM-LT)

Day-to-day science within the LiSyM is overseen and directed by the the LiSyM Scientific Leadership Team. This coordination team comprises the pillar coordinators and additional LiSyM members, and ensures smooth interaction between multi-skilled groups, often working in different institutions and across significant distances within Germany.

Programme: LiSyM: Liver Systems Medicine

Public web page: http://www.lisym.org/who-we-are

Molecular Steatosis - Imaging & Modeling (LiSyM-MSIM)

Dr. Nachiket Vartak (TU University, Dortmund) investigates the role of a particular protein - the GTPase Rab18 - in initiating NAFLD. He tries to influence Rab18 pharmacologically so that NAFLD is not initiated. Vartak also analyzes how bile acids leave the liver. He hopes to find ways to improve the flow of bile in a liver with dysfunctional bile flow.

Programme: LiSyM: Liver Systems Medicine

Public web page: http://www.lisym.org/our-work/junior-group/the-protein-rab18

Start date: 1st Jan 2016

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How histopathologic changes in pediatric nonalcoholic fatty liver disease influence in vivo liver stiffness.
LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi)

Abstract (Expand)

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents. About 30% of patients with NAFLD progress to the more severe condition of nonalcoholic … steatohepatitis (NASH), which is typically diagnosed using liver biopsy. Liver stiffness (LS) quantified by elastography is a promising imaging marker for the noninvasive assessment of NAFLD and NASH in pediatric patients. However, the link between LS and specific histopathologic features used for clinical staging of NAFLD is not well defined. Furthermore, LS data reported in the literature can vary greatly due to the use of different measurement techniques. Uniquely, time-harmonic elastography (THE) based on ultrasound and magnetic resonance elastography (MRE) use the same mechanical stimulation, allowing us to compare LS in biopsy-proven NAFLD previously determined by THE and MRE in 67 and 50 adolescents, respectively. In the present work, we analyzed the influence of seven distinct histopathologic features on LS, including septal infiltration, bridging fibrosis, pericellular fibrosis, hepatocellular ballooning, portal inflammation, lobular inflammation, and steatosis. LS was highly correlated with periportal and lobular fibrosis as well as hepatocellular ballooning while no independent association was found for inflammation and steatosis. Based on this analysis, we propose a composite elastography score (CES) which includes the four key histopathologic features identified as mechanically relevant. Interestingly, CES-relevant histopathologic features were associated with zonal distribution patterns of pediatric NAFLD. Mechano-structural changes associated with NAFLD progression can be histopathologically staged using the CES, which is easily determined noninvasively based on LS measured by time-harmonic elastography.

Authors: C. A. Hudert, H. Tzschatzsch, B. Rudolph, C. Loddenkemper, H. G. Holzhutter, L. Kalveram, S. Wiegand, J. Braun, I. Sack, J. Guo

Date Published: 17th Jan 2021

Publication Type: Journal

Regulation of the cytochrome P450 epoxyeicosanoid pathway is associated with distinct histologic features in pediatric non-alcoholic fatty liver disease.
LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi)

Abstract (Expand)

Non-alcoholic fatty liver disease (NAFLD) is a significant health burden in obese children for which there is currently no specific therapy. Preclinical studies indicate that epoxyeicosanoids, a class … of bioactive lipid mediators that are generated by cytochrome P450 (CYP) epoxygenases and inactivated by the soluble epoxide hydrolase (sEH), play a protective role in NAFLD. We performed a comprehensive lipidomics analysis using liver tissue and blood samples of 40 children with NAFLD. Proteomics was performed to determine CYP epoxygenase and sEH expressions. Hepatic epoxyeicosanoids significantly increased with higher grades of steatosis, while their precursor PUFAs were unaltered. Concomitantly, total CYP epoxygenase activity increased while protein level and activity of sEH decreased. In contrast, hepatic epoxyeicosanoids showed a strong decreasing trend with higher stages of fibrosis, accompanied by a decrease of CYP epoxygenase activity and protein expression. These findings suggest that the CYP epoxygenase/sEH pathway represents a potential pharmacologic target for the treatment of NAFLD.

Authors: L. Kalveram, W. H. Schunck, M. Rothe, B. Rudolph, C. Loddenkemper, H. G. Holzhutter, S. Henning, P. Bufler, M. Schulz, D. Meierhofer, I. W. Zhang, K. H. Weylandt, S. Wiegand, C. A. Hudert

Date Published: 4th Jan 2021

Publication Type: Journal

Changes in Liver Mechanical Properties and Water Diffusivity During Normal Pregnancy Are Driven by Cellular Hypertrophy.
LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi)

Abstract (Expand)

During pregnancy, the body's hyperestrogenic state alters hepatic metabolism and synthesis. While biochemical changes related to liver function during normal pregnancy are well understood, … pregnancy-associated alterations in biophysical properties of the liver remain elusive. In this study, we investigated 26 ex vivo fresh liver specimens harvested from pregnant and non-pregnant rats by diffusion-weighted imaging (DWI) and magnetic resonance elastography (MRE) in a 0.5-Tesla compact magnetic resonance imaging (MRI) scanner. Water diffusivity and viscoelastic parameters were compared with histological data and blood markers. We found livers from pregnant rats to have (i) significantly enlarged hepatocytes (26 +/- 15%, p < 0.001), (ii) increased liver stiffness (12 +/- 15%, p = 0.012), (iii) decreased viscosity (-23 +/- 14%, p < 0.001), and (iv) increased water diffusivity (12 +/- 11%, p < 0.001). In conclusion, increased stiffness and reduced viscosity of the liver during pregnancy are mainly attributable to hepatocyte enlargement. Hypertrophy of liver cells imposes fewer restrictions on intracellular water mobility, resulting in a higher hepatic water diffusion coefficient. Collectively, MRE and DWI have the potential to inform on structural liver changes associated with pregnancy in a clinical context.

Authors: K. Garczynska, H. Tzschatzsch, A. A. Kuhl, A. S. Morr, L. Lilaj, A. Hackel, E. Schellenberger, N. Berndt, H. G. Holzhutter, J. Braun, I. Sack, J. Guo

Date Published: 17th Dec 2020

Publication Type: Journal

Metabolic heterogeneity of human hepatocellular carcinoma: implications for personalized pharmacological treatment.
LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi)

Abstract (Expand)

Metabolic reprogramming is a characteristic feature of cancer cells, but there is no unique metabolic program for all tumors. Genetic and gene expression studies have revealed heterogeneous inter- and … intratumor patterns of metabolic enzymes and membrane transporters. The functional implications of this heterogeneity remain often elusive. Here, we applied a systems biology approach to gain a comprehensive and quantitative picture of metabolic changes in individual hepatocellular carcinoma (HCC). We used protein intensity profiles determined by mass spectrometry in samples of 10 human HCCs and the adjacent noncancerous tissue to calibrate Hepatokin1, a complex mathematical model of liver metabolism. We computed the 24-h profile of 18 metabolic functions related to carbohydrate, lipid, and nitrogen metabolism. There was a general tendency among the tumors toward downregulated glucose uptake and glucose release albeit with large intertumor variability. This finding calls into question that the Warburg effect dictates the metabolic phenotype of HCC. All tumors comprised elevated beta-oxidation rates. Urea synthesis was found to be consistently downregulated but without compromising the tumor's capacity for ammonia detoxification owing to increased glutamine synthesis. The largest intertumor heterogeneity was found for the uptake and release of lactate and the size of the cellular glycogen content. In line with the observed metabolic heterogeneity, the individual HCCs differed largely in their vulnerability against pharmacological treatment with metformin. Taken together, our approach provided a comprehensive and quantitative characterization of HCC metabolism that may pave the way for a computational a priori assessment of pharmacological therapies targeting metabolic processes of HCC.

Authors: N. Berndt, J. Eckstein, N. Heucke, T. Wuensch, R. Gajowski, M. Stockmann, D. Meierhofer, H. G. Holzhutter

Date Published: 8th Oct 2020

Publication Type: Journal

Functional consequences of metabolic zonation in murine livers: New insights for an old story.
LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi)

Abstract (Expand)

BACKGROUND & AIMS: Zone-dependent differences in the expression of metabolic enzymes along the porto-central axis of the acinus are a long-known feature of liver metabolism. A prominent example is … the preferential localization of the enzyme glutamine synthetase in pericentral hepatocytes, where it converts potentially toxic ammonia to the valuable amino acid glutamine. However, with the exception of a few key regulatory enzymes, a comprehensive and quantitative assessment of zonal differences in the abundance of metabolic enzymes and much more importantly, an estimation of the associated functional differences between portal and central hepatocytes is missing thus far. APPROACH & RESULTS: We addressed this problem by establishing a new method for the separation of periportal and pericentral hepatocytes that yields sufficiently pure fractions of both cell populations. Quantitative shotgun proteomics identified hundreds of differentially expressed enzymes in the two cell populations. We used zone-specific proteomics data for scaling of the maximal activities to generate portal and central instantiations of a comprehensive kinetic model of central hepatic metabolism (Hepatokin1). CONCLUSION: The model simulations revealed significant portal-to-central differences in almost all metabolic pathways involving carbohydrates, fatty acids, amino acids and detoxification.

Authors: N. Berndt, E. Kolbe, R. Gajowski, J. Eckstein, F. Ott, D. Meierhofer, H. G. Holzhutter, M. Matz-Soja

Date Published: 14th Apr 2020

Publication Type: Not specified

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