Pneumosepsis survival in the setting of obesity leads to persistent steatohepatitis and metabolic dysfunction.

Autor:	Kumar AJ; Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan School of Medicine, Ann Arbor, Michigan, USA., Parthasarathy C; Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan School of Medicine, Ann Arbor, Michigan, USA., Prescott HC; Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.; VA Center for Clinical Management Research, Ann Arbor, Michigan, USA., Denstaedt SJ; Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan School of Medicine, Ann Arbor, Michigan, USA., Newstead MW; Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan School of Medicine, Ann Arbor, Michigan, USA., Bridges D; Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan, USA., Bustamante A; Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan School of Medicine, Ann Arbor, Michigan, USA., Singer K; Department of Pediatrics, Division of Endocrinology, University of Michigan School of Medicine, Ann Arbor, Michigan, USA., Singer BH; Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
Jazyk:	angličtina
Zdroj:	Hepatology communications [Hepatol Commun] 2023 Aug 09; Vol. 7 (9). Date of Electronic Publication: 2023 Aug 09 (Print Publication: 2023).
DOI:	10.1097/HC9.0000000000000210
Abstrakt:	Background: As critical care practice evolves, the sepsis survivor population continues to expand, often with lingering inflammation in many organs, including the liver. Given the concurrently increasing population of patients with NAFLD, in this study, we aimed to understand the long-term effect of sepsis on pre-existing NAFLD and hyperglycemia. Methods: Male mice were randomized to a high-fat diet or a control diet (CD). After 24 weeks on diet, mice were inoculated with Klebsiella pneumoniae (Kpa). Serial glucose tolerance tests, and insulin and pyruvate challenge tests were performed 1 week before infection and at 2 and 6 weeks after infection. Whole tissue RNA sequencing and histological evaluation of the liver were performed. To test whether persistent inflammation could be reproduced in other abnormal liver environments, mice were also challenged with Kpa after exposure to a methionine-choline-deficient high-fat diet. Finally, a retrospective cohort of 65,139 patients was analyzed to evaluate whether obesity was associated with liver injury after sepsis. Results: After Kpa inoculation, high-fat diet mice had normalized fasting blood glucose without a change in insulin sensitivity but with a notable decrease in pyruvate utilization. Liver examination revealed focal macrophage collections and a unique inflammatory gene signature on RNA analysis. In the clinical cohort, preobesity, and class 1 and class 2 obesity were associated with increased odds of elevated aminotransferase levels 1-2 years after sepsis. Conclusions: The combination of diet-induced obesity and pneumosepsis survival in a murine model resulted in unique changes in gluconeogenesis and liver inflammation, consistent with the progression of benign steatosis to steatohepatitis. In a cohort study, obese patients had an increased risk of elevated aminotransferase levels 1-2 years following sepsis. (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)
Databáze:	MEDLINE
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