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Peroxisomal β-oxidation regulates whole body metabolism, inflammatory vigor, and pathogenesis of nonalcoholic fatty liver disease
Maria E. Moreno-Fernandez, … , Kasper Hoebe, Senad Divanovic
Maria E. Moreno-Fernandez, … , Kasper Hoebe, Senad Divanovic
Published March 22, 2018
Citation Information: JCI Insight. 2018;3(6):e93626. https://doi.org/10.1172/jci.insight.93626.
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Research Article Inflammation Metabolism

Peroxisomal β-oxidation regulates whole body metabolism, inflammatory vigor, and pathogenesis of nonalcoholic fatty liver disease

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Abstract

Nonalcoholic fatty liver disease (NAFLD), a metabolic predisposition for development of hepatocellular carcinoma (HCC), represents a disease spectrum ranging from steatosis to steatohepatitis to cirrhosis. Acox1, a rate-limiting enzyme in peroxisomal fatty acid β-oxidation, regulates metabolism, spontaneous hepatic steatosis, and hepatocellular damage over time. However, it is unknown whether Acox1 modulates inflammation relevant to NAFLD pathogenesis or if Acox1-associated metabolic and inflammatory derangements uncover and accelerate potential for NAFLD progression. Here, we show that mice with a point mutation in Acox1 (Acox1Lampe1) exhibited altered cellular metabolism, modified T cell polarization, and exacerbated immune cell inflammatory potential. Further, in context of a brief obesogenic diet stress, NAFLD progression associated with Acox1 mutation resulted in significantly accelerated and exacerbated hepatocellular damage via induction of profound histological changes in hepatocytes, hepatic inflammation, and robust upregulation of gene expression associated with HCC development. Collectively, these data demonstrate that β-oxidation links metabolism and immune responsiveness and that a better understanding of peroxisomal β-oxidation may allow for discovery of mechanisms central for NAFLD progression.

Authors

Maria E. Moreno-Fernandez, Daniel A. Giles, Traci E. Stankiewicz, Rachel Sheridan, Rebekah Karns, Monica Cappelletti, Kristin Lampe, Rajib Mukherjee, Christian Sina, Anthony Sallese, James P. Bridges, Simon P. Hogan, Bruce J. Aronow, Kasper Hoebe, Senad Divanovic

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Figure 1

Acox1Lampe1 mutation promotes proinflammatory immune responsiveness.

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Acox1Lampe1 mutation promotes proinflammatory immune responsiveness.
(A ...
(A and B) Twelve-week-old, chow diet–fed, Acox1Lampe1 mice and WT littermate controls were challenged i.p. with biotinylated capture Ab (20 μg/mouse) 3 hours prior to i.v. saline (NS) or LPS challenge (25 μg/mouse; ultrapure E. coli 0111:B4). Twenty-four hours later, serum was collected, and IL-6, TNF-α, IFN-γ, and IL-17A levels were quantified by IVCCA ELISA. (C) Supernatant IL-6 and IL-1β levels from BM-derived DCs (BMDC), of chow diet–fed, Acox1Lampe1 mice and WT littermate controls stimulated for 24 hours with saline (NS) or LPS (100 ng/ml). (D) Splenic naive CD4+ T cells from chow diet–fed WT mice, isolated by negative selection using magnetic beads, were cultured under Th17 and Th1 polarizing conditions with or without peroxisomal β-oxidation inhibitor (thioridizine, 1 μM) and the frequency of IL-17A– and IFN-γexpressing cells were quantified by flow cytometry. (E and F) Splenic naive CD4+ T cells from 12-week-old, chow diet–fed, Acox1Lampe1 mice and WT littermate controls, isolated by negative selection using magnetic beads, were cultured under Th17 and Th1 polarizing conditions, and the frequency of IL-17A– and IFN-γ–expressing cells was quantified by flow cytometry. (G) Frequency of total splenic Th1 (CD3+CD4+IFN-γ+IL-17A–), Th17 (CD3+CD4+IL-17A+IFN-γ–), and Treg (CD3+CD4+FOXP3+) in chow diet–fed Acox1Lampe1 mice and WT littermate controls. Data represent means ± SEM. (A, B, and E–G) Unpaired Student’s t test; *P < 0.05, **P < 0.01. (C) One-way ANOVA followed by Tukey’s correction; *P < 0.05. White bars denote WT mice; black bars denote Acox1Lampe1 mice. (A, B and D) Data combined from 2 independent experiments, n = 3–8/condition. (C and E) Data combined from 2 independent experiments, n = 7/condition. (F and G) A single experiment, n = 3–4/condition.

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