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
View: Text | PDF
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

×

Figure 5

Myeloid FoxO1 depletion protects against diet-induced NASH.

Options: View larger image (or click on image) Download as PowerPoint
Myeloid FoxO1 depletion protects against diet-induced NASH. MøFoxO1-KO a...
MøFoxO1-KO and WT littermates (male, 6 weeks old) were fed a NASH diet for 25 weeks. (A) Body weight. (B) Glucose tolerance test. (C) Insulin tolerance test. (D) Fasting blood glucose levels. (E) Fasting plasma insulin levels. Fasting blood glucose and plasma insulin levels were measured in mice after 16-hour fasting. (F) HOMA-IR. (G) Plasma cholesterol levels. (H) Plasma TG levels. Both groups of mice were euthanized after 16-hour fasting following 25 weeks of NASH diet feeding. Liver tissues were procured for histological examination. (I) H&E staining of liver sections (original magnification, ×20). Scale bars: 100 μm. (J) Hepatic TG content. (K) Hepatic cholesterol content. (L) H&E staining of liver sections (original magnification, ×10). Scale bars: 100 μm. (M) Oil Red O staining of liver sections (original magnification, ×10). Scale bars: 100 μm. (N) NASH score (NAS). (O) Lobular inflammation. Data are expressed as mean ± SEM (n = 6–11). Statistical analysis in A–H, J, K, N, and O was performed using a 2-tailed, unpaired t test. *P < 0.05, **P < 0.01.