title: Synergy analysis reveals association between insulin signaling and desmoplakin expression in palmitate treated HepG2 cells.
abstract: The regulation of complex cellular activities in palmitate treated HepG2 cells, and the ensuing cytotoxic phenotype, involves cooperative interactions between genes. While previous approaches have largely focused on identifying individual target genes, elucidating interacting genes has thus far remained elusive. We applied the concept of information synergy to reconstruct a "gene-cooperativity" network for palmititate-induced cytotoxicity in liver cells. Our approach integrated gene expression data with metabolic profiles to select a subset of genes for network reconstruction. Subsequent analysis of the network revealed insulin signaling as the most significantly enriched pathway, and desmoplakin (DSP) as its top neighbor. We determined that palmitate significantly reduces DSP expression, and treatment with insulin restores the lost expression of DSP. Insulin resistance is a common pathological feature of fatty liver and related ailments, whereas loss of DSP has been noted in liver carcinoma. Reduced DSP expression can lead to loss of cell-cell adhesion via desmosomes, and disrupt the keratin intermediate filament network. Our findings suggest that DSP expression may be perturbed by palmitate and, along with insulin resistance, may play a role in palmitate induced cytotoxicity, and serve as potential targets for further studies on non-alcoholic fatty liver disease (NAFLD).
authors: Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, Michigan, United States of America.
authors: Xuewei
authors: X
authors: Wang
authors: Aritro
authors: A
authors: Nath
authors: Xuerui
authors: X
authors: Yang
authors: Amanda
authors: A
authors: Portis
authors: S Patrick
authors: SP
authors: Walton
authors: Christina
authors: C
authors: Chan
mesh_terms: D016923:Cell Death / Q000187:drug effects; D051180:Desmoplakins / Q000235:genetics* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000235:genetics*; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D010168:Palmitates / Q000494:pharmacology*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*
chemical_list: D051180:Desmoplakins; D007328:Insulin; D010168:Palmitates