Myeloid FoxO1 depletion attenuates hepatic inflammation and prevents nonalcoholic steatohepatitis
Sojin Lee, Taofeek O. Usman, Jun Yamauchi, Goma Chhetri, Xingchun Wang, Gina M. Coudriet, Cuiling Zhu, Jingyang Gao, Riley McConnell, Kyler Krantz, Dhivyaa Rajasundaram, Sucha Singh, Jon Piganelli, Alina Ostrowska, Alejandro Soto-Gutierrez, Satdarshan P. Monga, Aatur D. Singhi, Radhika Muzumdar, Allan Tsung, H. Henry Dong
Sojin Lee, Taofeek O. Usman, Jun Yamauchi, Goma Chhetri, Xingchun Wang, Gina M. Coudriet, Cuiling Zhu, Jingyang Gao, Riley McConnell, Kyler Krantz, Dhivyaa Rajasundaram, Sucha Singh, Jon Piganelli, Alina Ostrowska, Alejandro Soto-Gutierrez, Satdarshan P. Monga, Aatur D. Singhi, Radhika Muzumdar, Allan Tsung, H. Henry Dong
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Research Article Endocrinology Metabolism

Myeloid FoxO1 depletion attenuates hepatic inflammation and prevents nonalcoholic steatohepatitis

Abstract

Hepatic inflammation is culpable for the evolution of asymptomatic steatosis to nonalcoholic steatohepatitis (NASH). Hepatic inflammation results from abnormal macrophage activation. We found that FoxO1 links overnutrition to hepatic inflammation by regulating macrophage polarization and activation. FoxO1 was upregulated in hepatic macrophages, correlating with hepatic inflammation, steatosis, and fibrosis in mice and patients with NASH. Myeloid cell conditional FoxO1 knockout skewed macrophage polarization from proinflammatory M1 to the antiinflammatory M2 phenotype, accompanied by a reduction in macrophage infiltration in liver. These effects mitigated overnutrition-induced hepatic inflammation and insulin resistance, contributing to improved hepatic metabolism and increased energy expenditure in myeloid cell FoxO1–knockout mice on a high-fat diet. When fed a NASH-inducing diet, myeloid cell FoxO1–knockout mice were protected from developing NASH, culminating in a reduction in hepatic inflammation, steatosis, and fibrosis. Mechanistically, FoxO1 counteracts Stat6 to skew macrophage polarization from M2 toward the M1 signature to perpetuate hepatic inflammation in NASH. FoxO1 appears to be a pivotal mediator of macrophage activation in response to overnutrition and a therapeutic target for ameliorating hepatic inflammation to stem the disease progression from benign steatosis to NASH.

Authors

Sojin Lee, Taofeek O. Usman, Jun Yamauchi, Goma Chhetri, Xingchun Wang, Gina M. Coudriet, Cuiling Zhu, Jingyang Gao, Riley McConnell, Kyler Krantz, Dhivyaa Rajasundaram, Sucha Singh, Jon Piganelli, Alina Ostrowska, Alejandro Soto-Gutierrez, Satdarshan P. Monga, Aatur D. Singhi, Radhika Muzumdar, Allan Tsung, H. Henry Dong

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Figure 4

Myeloid FoxO1 depletion improves energy expenditure and ameliorates steatosis in dietary obese mice.

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Myeloid FoxO1 depletion improves energy expenditure and ameliorates stea...
MøFoxO1-KO and WT littermates (male, 8 weeks old) were fed an HFD for 34 weeks, followed by the determination of energy expenditure. (A) Respiratory exchange ratio (RER) in dark and light cycles. (B) VO2 consumption rates in dark and light cycles. (C) Oil Red O staining of liver sections of WT mice (original magnification, ×20). Scale bar: 50 μm. (D) Oil Red O staining of liver sections of MøFoxO1-KO mice (original magnification, ×20). Scale bar: 50 μm. (E) Hepatic TG content. (F) Hepatic expression of key lipogenic genes, as determined by real-time qRT-PCR assay. (G) Hepatic expression of key genes in fatty acid oxidation. (H) Hepatic expression of genes in VLDL-TG production. Data are expressed as mean ± SEM (n = 7–9). Statistical analysis in A, B, and H was performed using a 1-tailed, unpaired t test, and in E–G using a 2-tailed, unpaired t test. *P < 0.05, **P < 0.01.