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

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

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 4

Short-term obesogenic-diet challenge accelerates and exacerbates Acox1Lampe1 mutation–driven hepatocellular damage and systemic inflammation.

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Short-term obesogenic-diet challenge accelerates and exacerbates Acox1La...
Eight-week-old Acox1Lampe1 mice and WT littermate controls were fed a HFHCD or chow diet for 4 weeks. (A) Weight gain. (B) Liver/body mass ratio. (C) Serum ALT levels. (D) Representative liver histology (H&E staining; 20x). (E) Total hepatic immune (CD45+) cell infiltration determined by flow cytometry. (F) Hepatic chemokine mRNA expression of Ccl2, Ccl3, Ccl4, Ccl22, and Cxcl10. (G) Hepatic TG levels. (H) Hepatic lipid content measured by thin layer chromatography and visualized by primuline staining. Cholesterol ester (CE), triglyceride (TG), diacylglycerol (DAG), free cholesterol (FC), monoacylglycerol (MAG), phospholipids (polar). Data represent means ± SEM. (A, E and F) Unpaired Student’s t test; *P < 0.05, **P < 0.01, ***P < 0.01. (B, C, and G) One-way ANOVA followed by Tukey’s correction; *P < 0.05, **P < 0.01, ***P < 0.01. (A) White squares denote WT mice fed chow diet; white circles denote WT mice fed HFHCD; black squares denote Acox1Lampe1 mice fed chow diet; black circles denote Acox1Lampe1 mice fed HFHCD. (B, C, and E–G) White bars denote WT mice fed HFHCD; black bars denote Acox1Lampe1 mice fed HFHCD. (A) Representative of 2 individual experiments, n = 3/condition. (B, C, F and G) Data combined from 2 independent experiments, n = 6–9/condition. (E and H) A single experiment, n = 3/condition.