Deciphering hepatocellular responses to metabolic and oncogenic stress

Authors

  • Kathrina L. Marcelo Baylor College of Medicine
  • Fumin Lin Baylor College of Medicine
  • Kimal Rajapakshe Baylor College of Medicine
  • Adam Dean Baylor College of Medicine
  • Naomi Gonzales Baylor College of Medicine
  • Cristian Coarfa Baylor College of Medicine
  • Anthony R. Means Baylor College of Medicine
  • Lauren C. Goldie Baylor College of Medicine
  • Brian York Baylor College of Medicine

DOI:

https://doi.org/10.14440/jbm.2015.77

Keywords:

endothelium, hepatocytes, liver cancer, macrophages, obesity

Abstract

Each cell type responds uniquely to stress and fractionally contributes to global and tissue-specific stress responses. Hepatocytes, liver macrophages (MΦ), and sinusoidal endothelial cells (SEC) play functionally important and interdependent roles in adaptive processes such as obesity and tumor growth. Although these cell types demonstrate significant phenotypic and functional heterogeneity, their distinctions enabling disease-specific responses remain understudied. We developed a strategy for the simultaneous isolation and quantification of these liver cell types based on antigenic cell surface marker expression. To demonstrate the utility and applicability of this technique, we quantified liver cell-specific responses to high-fat diet (HFD) or diethylnitrosamine (DEN), a liver-specific carcinogen, and found that while there was only a marginal increase in hepatocyte number, MΦ and SEC populations were quantitatively increased. Global gene expression profiling of hepatocytes, MΦ and SEC identified characteristic gene signatures that define each cell type in their distinct physiological or pathological states. Integration of hepatic gene signatures with available human obesity and liver cancer microarray data provides further insight into the cell-specific responses to metabolic or oncogenic stress. Our data reveal unique gene expression patterns that serve as molecular “fingerprints” for the cell-centric responses to pathologic stimuli in the distinct microenvironment of the liver. The technical advance highlighted in this study provides an essential resource for assessing hepatic cell-specific contributions to metabolic and oncogenic stress, information that could unveil previously unappreciated molecular mechanisms for the cellular crosstalk that underlies the continuum from metabolic disruption to obesity and ultimately hepatic cancer.

Author Biography

Brian York, Baylor College of Medicine

Assistant Professor

Department of Molecular and Cellular Biology

Our research is focused on understanding the physiological contributions of transcriptional coregulators and their upstream signaling inputs. The majority of our research is geared toward unraveling the metabolic and inflammatory pathways involved in liver homeostasis and disease. Over the past decade, we have defined the Steroid Receptor Coactivator (SRC) family as master gatekeepers of systems metabolism. We utilize a variety of in vitro and in vivo models to elucidate novel functions of these potent transcriptional regulators.

In search of the upstream signaling inputs to the SRCs, we have recently identified the calcium kinase signaling cascade as a major player. These studies have evolved into a new research arm of the laboratory that is dedicated to understanding perturbations in calcium signaling as it pertains to hepatic metabolism, inflammation and angiogenesis. Importantly, this triad of processes are central to the development of metabolically induced pathologies beginning with Non Alcoholic Fatty Liver Disease (NAFLD) that progresses to Non Alcoholic Steatohepatitis (NASH) and ultimately to Hepatocellular Carcinoma (HCC).

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Published

2015-10-08

How to Cite

1.
Marcelo KL, Lin F, Rajapakshe K, Dean A, Gonzales N, Coarfa C, Means AR, Goldie LC, York B. Deciphering hepatocellular responses to metabolic and oncogenic stress. J Biol Methods [Internet]. 2015Oct.8 [cited 2021Sep.18];2(3):e28. Available from: https://jbmethods.org/jbm/article/view/77

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