Macrophage-specific Fatp4 deletion exacerbates HFHC-induced NASH via a shift towards M2 polarization

Background Mutations of fatty acid transport protein 4 (FATP4) cause ichthyosis prematurity syndrome (IPS) characterized by skin lesions and associated with eosinophilia and allergies. We hypothesized that FATP4 may have biological functions in immune cells, particularly macrophages, as M2 macrophages are known to mediate allergic inflammation. Therefore, lysM-Cre Fatp4 deficient (KO) mice were generated and subjected to high-fat/high-cholesterol (HFHC) diet as a model of non-alcoholic steatohepatitis (NASH) and chronic stress.

Methods KO and C57BL/6 control mice at one year of age were subjected to HFHC feeding for 16 weeks. Histological analysis of mouse livers was performed. Plasma cytokines and liver transaminases were measured. Lipid assays of plasma and livers were performed.

Results Upon HFHC feeding, male KO mice showed a > 2-fold increase of spleen weight. These KO presented a significant increase of liver lipid vesicles, but a decrease of plasma triglycerides (TG) and fatty acids (NEFA). Under HFHC feeding, female KO mice showed a moderate increase of liver and spleen weights. By histological analysis of livers, these female mice displayed massive infiltration of immune cells. These mice showed a decrease of TG and NEFA in livers and plasma. Thus, macrophage-specific Fatp4 deficiency under HFHC induced more prominent splenomegaly in males. While male mutants presented increased liver steatosis, female mutants showed decreased liver lipids associated with accumulation of immune cells. HFHC-fed KO mice showed an increase of plasma M2/Th2 markers IL-4 and IL-13 by ~5 folds for females and by ~3 and ~4 folds for males, respectively. Both male and female mutants showed an increase of chemotactic factor MCP-1, whereas only female mutants presented an elevation of IL-5 and IL-6. Hence, compared with male mutants, female mutants showed a larger increase of IL-4 and IL-13 as well as an additional increase of IL-5 and IL-6. Notably, TNF-α was significantly decreased in plasma of both male and female mutants, supporting a shift from M1 towards M2 polarization upon HFHC feeding.

Conclusions Under HFHC, macrophage Fatp4 deficiency in males exacerbated hepatic steatosis, whereas the deficiency in females induced progression to NASH. While the increase of M2/Th2 markers is consistent with allergies, the increase of eosinophil chemoattractant IL-5 observed in female mutants is in line with eosinophilia reported in IPS patients with FATP4 mutations.

Publication History

Article published online:
04 January 2021