Biology subjects

Hetzer, J.

Publications and source records attributed to Hetzer, J..

3 recordsLinked to original sources

bioRxiv2023

Beneficial effects of intermittent fasting in NASH and subsequent HCC development are executed by concerted PPAR alpha and PCK1 action in hepatocytes

The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen (two non-consecutive days of food deprivation per week), initiated in the active phase of mice, prevents/ameliorates NASH and fibrosis as well as reduces subsequent HCC development without affecting total calorie intake. The timing, length and number of fasting cycles as well as the type of NASH diet were all critical parameters determining the effectiveness of the fasting benefits. Combined proteomic, transcriptomic and metabolomic analyses identified that PPAR and glucocorticoid receptor (GR)-PCK1 act co-operatively as hepatic executors of the fasting response by promoting fatty acid catabolism and gluconeogenesis whilst suppressing anabolic lipogenesis. In line, PPAR targets and PCK1 were reduced in human NASH. Additionally, dynamic [18F]FDG-PET analysis in vivo revealed increased [18F]FDG uptake/retention and enhanced gluconeogenesis in the liver upon fasting (in accordance with PPAR and GR-PCK1 activation) when assessed by compartmental modelling. Hepatocyte-specific GR deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis, confirming their causal relationship in integrating systemic signalling in hepatocytes. Notably, PPAR agonist pemafibrate recapitulated key aspects of hepatic fasting signalling at a molecular level. Therefore, IF or pharmacological mimetics of the PPAR and/or GR-PCK1 axis could be a viable intervention against NASH and subsequent liver cancer. One-Sentence SummaryIntermittent fasting protects against fatty liver disease and liver cancer through concerted PPAR and GR-PCK1 action in hepatocytes.

cancer biology↗

bioRxiv2023

Phenotypic drought stress prediction of European beech (Fagus sylvatica) by genomic prediction and remote sensing

Current climate change species response models usually not include evolution. We integrated remote sensing with population genomics to improve phenotypic response prediction to drought stress in the key forest tree European beech (Fagus sylvatica L.). We used whole-genome sequencing of pooled DNA from natural stands along an ecological gradient from humid-cold to warm-dry climate. We phenotyped stands for leaf area index (LAI) and moisture stress index (MSI) for the period 2016-2022. We predicted this data with matching meteorological data and a newly developed genomic population prediction score in a Generalised Linear Model. Model selection showed that addition of genomic prediction decisively increased the explanatory power. We then predicted the response of beech to future climate change under evolutionary adaptation scenarios. A moderate climate change scenario would allow persistence of adapted beech forests, but not worst-case scenarios. Our approach can thus guide mitigation measures, such as allowing natural selection or proactive evolutionary management.

evolutionary biology↗

bioRxiv2021

Epithelial cells of the intestine acquire cell-intrinsic inflammation signatures during ageing

During ageing, cell-intrinsic and extrinsic factors lead to the decline of tissue function and organismal health. Disentangling these factors is important for developing effective strategies to prolong organismal healthspan. Here, we addressed this question in the mouse intestinal epithelium, which forms a dynamic interface with its microenvironment and receives extrinsic signals affecting its homeostasis and tissue ageing. We systematically compared transcriptional profiles of young and aged epithelial cells in vivo and ex vivo in cultured intestinal organoids. We found that all cell types of the aged epithelium exhibit an inflammation phenotype, which is marked by MHC class II upregulation and most pronounced in enterocytes. This was accompanied by elevated levels of the immune tolerance markers PD-1 and PD-L1 in the aged tissue microenvironment, indicating dysregulation of immunological homeostasis. Intestinal organoids from aged mice still showed an inflammation signature after weeks in culture, which was concurrent with increased chromatin accessibility of inflammation-associated loci. Our results reveal a cell-intrinsic, persistent inflammation phenotype in aged epithelial cells, which might contribute to systemic inflammation observed during ageing.

genomics↗