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J Hepatol. 2019 Jan 21. pii: S0168-8278(19)30027-3. doi: 10.1016/j.jhep.2018.12.037. [Epub ahead of print]

Hepatic PPARα is critical in the metabolic adaptation to sepsis.

Author information

1
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France.
2
Laboratory of Critical Care Medicine, Dept Cellular and Molecular Medicine, KU Leuven, University Hospitals Leuven, Herestraat 49 Bus 503, B-3000 Leuven, Belgium.
3
Center for Integrative Genomics, Université de Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland.
4
Maastricht University, Dept. of Internal Medicine, Maastricht, The Netherlands.
5
Institut National de La Recherche Agronomique (INRA), UMR1331 ToxAlim, Toulouse, France.
6
Institut National de La Santé et de La Recherche Médicale (INSERM), UMR1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
7
Institut National de La Santé et de La Recherche Médicale (INSERM), UMR1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France; Institut National de La Recherche Agronomique (INRA), UMR1331 ToxAlim, Toulouse, France.
8
Institut National de La Recherche Agronomique (INRA), UMR1331 ToxAlim, Toulouse, France; Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, 11 Mandalay Road 308232, Singapore; Center for Integrative Genomics, Université de Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland.
9
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France. Electronic address: bart.staels@pasteur-lille.fr.

Abstract

BACKGROUND AND AIMS:

Although the role of inflammation to combat infection is known, the contribution of metabolic changes in response to sepsis is poorly understood. Sepsis induces the release of lipid mediators, many of which activate nuclear receptors such as the peroxisome proliferator-activated receptor (PPAR)α, which controls both lipid metabolism and inflammation. However, the role of hepatic PPARα in the response to sepsis is unknown.

METHODS:

Sepsis was induced by intraperitoneal injection of Escherichia coli in different models of cell-specific Pparα-deficiency and their controls. The systemic and hepatic metabolic response was analysed using biochemical, transcriptomic and functional assays. PPARα expression was analysed in livers from elective surgery and critically ill patients and correlated with hepatic gene expression and blood parameters RESULTS: Both whole body and non-hematopoietic Pparα-deficiency in mice decreased survival upon bacterial infection. Livers of septic Pparα-deficient mice displayed an impaired metabolic shift from glucose to lipid utilization resulting in more severe hypoglycemia, impaired induction of hyperketonemia and increased steatosis due to lower expression of genes involved in fatty acid catabolism and ketogenesis. Hepatocyte-specific deletion of PPARα impaired the metabolic response to sepsis and was sufficient to decrease survival upon bacterial infection. Hepatic PPARA expression was lower in critically ill patients and correlated positively with expression of lipid metabolism genes, but not with systemic inflammatory markers.

CONCLUSION:

Metabolic control by PPARα in hepatocytes plays a key role in the host defense to infection. Lay summary: As the main cause of death of critically ill patients, sepsis remains a major health issue lacking efficacious therapies. While current clinical literature suggests an important role for inflammation, metabolic aspects of sepsis have been mostly overlooked. Here, we show that mice with an impaired metabolic response, due to deficiency of the nuclear receptor PPARα in the liver, exhibit enhanced mortality upon bacterial infection despite a similar inflammatory response, suggesting that metabolic interventions may be a viable strategy for improving sepsis outcomes.

KEYWORDS:

Hepatocytes; Inflammation; Metabolism; Nuclear receptors; Sepsis

PMID:
30677458
DOI:
10.1016/j.jhep.2018.12.037

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