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Cell Rep. 2017 Dec 12;21(11):3317-3328. doi: 10.1016/j.celrep.2017.11.059.

Hepatic Dysfunction Caused by Consumption of a High-Fat Diet.

Author information

1
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
3
Department of Cancer Biology, Department of Oncologic Pathology, and Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA.
4
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, Worcester, MA 01605, USA. Electronic address: roger.davis@umassmed.edu.
5
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: fraenkel-admin@mit.edu.

Abstract

Obesity is a major human health crisis that promotes insulin resistance and, ultimately, type 2 diabetes. The molecular mechanisms that mediate this response occur across many highly complex biological regulatory levels that are incompletely understood. Here, we present a comprehensive molecular systems biology study of hepatic responses to high-fat feeding in mice. We interrogated diet-induced epigenomic, transcriptomic, proteomic, and metabolomic alterations using high-throughput omic methods and used a network modeling approach to integrate these diverse molecular signals. Our model indicated that disruption of hepatic architecture and enhanced hepatocyte apoptosis are among the numerous biological processes that contribute to early liver dysfunction and low-grade inflammation during the development of diet-induced metabolic syndrome. We validated these model findings with additional experiments on mouse liver sections. In total, we present an integrative systems biology study of diet-induced hepatic insulin resistance that uncovered molecular features promoting the development and maintenance of metabolic disease.

KEYWORDS:

computational biology; high-fat diet; insulin resistance; integrative modeling; obesity; omic data; systems biology

PMID:
29241556
PMCID:
PMC5734865
DOI:
10.1016/j.celrep.2017.11.059
[Indexed for MEDLINE]
Free PMC Article

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