Deciphering hepatocellular responses to metabolic and oncogenic stress.
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.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Kathrina L
KL
Marcelo
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Fumin
F
Lin
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Kimal
K
Rajapakshe
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Adam
A
Dean
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Naomi
N
Gonzales
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Cristian
C
Coarfa
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA ; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Anthony R
AR
Means
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA ; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA ; USDA/ARS Children's Nutrition Research Center at Baylor College of Medicine, Houston, TX, USA.
Lauren C
LC
Goldie
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA ; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
Brian
B
York
endothelium; hepatocytes; liver cancer; macrophages; obesity