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Single Nucleus RNA Sequencing of Pre-Malignant Liver Reveals Disease-Associated Hepatocyte State with HCC Prognostic Potential

ABSTRACT: Current approaches to stage chronic liver diseases have limited utility to directly predict liver cancer risk. Here, we employed single nucleus RNA sequencing (snRNA-seq) to characterize the cellular microenvironment of healthy and chronically injured pre-malignant livers using two distinct mouse models. Analysis of 40,748 hepatic nuclei unraveled a previously uncharacterized disease-associated hepatocyte transcriptional state (daHep). These cells were absent in healthy livers, but were increasingly prevalent as chronic liver disease progressed towards hepatocarcinogenesis. Gene expression deconvolution of 1,439 human liver transcriptomes from publicly available datasets revealed that daHep frequencies highly correlate with current histopathological liver disease staging systems. Importantly, we show that high daHep levels precede carcinogenesis in mice and humans and predict a higher risk of hepatocellular carcinoma (HCC) development. This novel transcriptional signature with diagnostic and, more importantly, prognostic significance has the potential to change the way chronic liver disease patients are staged, surveilled and risk-stratified.

ORGANISM(S): Mus musculus

PROVIDER: GSE200366 | GEO | 2022/04/12

REPOSITORIES: GEO

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Murine Western diet-induced nonalcoholic steatohepatitis liver proteome

Project description:Non-alcoholic fatty liver disease (NAFLD) is the number one cause of chronic liver disease worldwide, with 25% of these patients developing nonalcoholic steatohepatitis (NASH). NASH significantly increases the risk of cirrhosis and decompensated liver failure. Past studies in rodent models have shown the knockout of glycine-N-methyltransferase (GNMT) results in rapid pro-gression of steatosis, fibrosis, and hepatocellular carcinoma. However, the attenuation of GNMT in subjects with NASH and the molecular basis for its impact on the disease process are still unclear. To address this knowledge gap, we show the reduction of GNMT protein levels in the liver of NASH subjects compared to healthy controls. To gain insight into the impact of decreased GNMT in the disease process, we performed global label-free proteome studies on the livers from a murine Western diet-based model of NASH. Histological and molecular characterization of the animal model demonstrate high resemblance to the human disease.

2022-04-04 | PXD030781 | Pride

Transcriptomic study of human liver biopsies in obese patients with low and high liver fat

Project description:Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. In this study liver metabolic activity and functionality in NAFLD was charted by integrating global transcriptomic data within a genome-scale model of human metabolism. Gene expression was measured in the human liver of eight subjects with extreme steatosis diagnosed with NAFLD (liver fat % range 20-80%), and eight healthy, but obese subjects with low liver fat content (liver fat % range 0-10%). This dataset is part of the TransQST collection.

2016-06-01 | E-MTAB-4231 | biostudies-arrayexpress

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2022-01-11 | GSE192741 | GEO

Spatial proteogenomics reveals distinct and evolutionarily-conserved hepatic macrophage niches (single cells)

2022-01-11 | GSE192740 | GEO

Chronic Alcohol Consumption Alters micro-RNA Radiation Responses in the Mouse Liver

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2016-03-15 | E-GEOD-79186 | biostudies-arrayexpress

Mapping the molecular signatures of diet-induced NASH and its regulation by the hepatokine Tsukushi

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2019-01-08 | GSE119340 | GEO

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| EGAS00001002983 | EGA

Transcriptional changes of adult liver biliary epithelial cells in vivo upon high-fat diet

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2023-03-22 | GSE217739 | GEO

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Project description:Chronic liver injury triggers complications such as liver fibrosis and hepatocellular carcinoma (HCC), which are associated with alterations in distinct signaling pathways. Of particular interest is the interaction between mechanisms controlled by IKKγ/NEMO, the regulatory IKK subunit, and Jnk activation for directing cell death and survival. In the present study, we aimed to define the relevance of Jnk in hepatocyte-specific NEMO knockout mice (NEMOΔhepa), a genetic model of chronic inflammatory liver injury. We generated global Jnk1-/-/NEMOΔhepa and Jnk2-/-/NEMOΔhepa mice by crossing NEMOΔhepa mice with Jnk1-/- and Jnk2-/- animals, respectively, and examined the progression of chronic liver disease. Moreover, we investigated the expression of Jnk during acute liver injury, evaluated the role of Jnk1 in bone marrow-derived cells, and analyzed the expression of NEMO and pJnk in human diseased-livers. Deletion of Jnk1 significantly aggravated the progression of liver disease, exacerbating apoptosis, compensatory proliferation and carcinogenesis in NEMOΔhepa mice. Jnk2-/-/NEMOΔhepa showed increased RIP-1 and RIP-3 expression and hepatic inflammation. Jnk1 in hematopoietic cells rather than hepatocytes had an impact on the progression of chronic liver disease in NEMOΔhepa livers. These findings are of clinical relevance since NEMO expression was down-regulated in hepatocytes of patients with HCC whereas NEMO and pJnk were expressed in a large amount of infiltrating cells. While Jnk1 is protective in NEMOΔhepa-depleted hepatocytes, Jnk1 in hematopoietic cells rather than hepatocytes is a crucial driver of hepatic injury. These results elucidate the complex function of Jnk in chronic inflammatory liver disease. Livers from global knockout mice for Jnk1 (Jnk1-/-) and Jnk2 (Jnk2-/- ), and double-knockout mice for Jnk1/NEMO (global Jnk1-/-/NEMOΔhepa) and Jnk2/NEMO (global Jnk2-/-/NEMOΔhepa), were subjected to gene expression profiling.

2015-06-22 | E-GEOD-59601 | biostudies-arrayexpress

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