aP2-specific inactivation of fatty acid transport protein 4 in mice sensitizes hepatic fibrogenesis under methionine and choline-deficient diet

Background/Aims: Fatty acid transport Protein 4 (FATP4) catalyzes activation of fatty acids into specific complex lipids, such as phospholipids and sphingolipids. It is known that FATP4 plays a major role in the skin by altering ceramide metabolism. We have previously shown that adipocyte-specific FATP4 deficiency (by using aP2-Cre FATP4KO mice) sensitizes with high-fat diet for an increase of body and adipose tissue weights concomitant with a manifestation of fatty liver. The latter could be due to an overspill of adipose fats or a presumed FATP4 effect on hepatic stellate cells and/or macrophages which are known to also express aP2. We therefore investigated the latter possibility by feeding aP2-Cre FATP4KO mice with methionine and choline-deficient (MCD) diet which is a fatty liver model with severe fibrosis and inflammation. Methods: WT and aP2-Cre FATP4KO female mice at ˜12 months old were fed with MCD diet for 4 weeks. Functional assays included transaminases, qRT-PCR, Western blot, histology, and immunohistochemistry (IHC).

Results: MCD diet feeding of WT and KO mice caused the same body weight loss, serum ALT and caspase 3 elevation, the extent of fatty liver, increased vimentin protein expression as well as elevated mRNA expression of PPARγ, TIMP1, smad7, and collagen 1a1/3a1/4a1. However, compared with MCD-fed WT MCD-fed KO mice exhibited aggravated hepatic fibrogenic response as revealed by an increase of Sirius-Red staining, α-smooth muscle actin by IHC and Western blot as well as mRNA expression of plasminogen activator inhibitor-1. Such effects were not observed for inflammatory markers including F4/80 by IHC and TNF-α mRNA expression, suggesting no involvement of macrophages in the observed MCD and FATP4 response. Notably, MCD feeding of WT mice caused a marked increase of mRNA and protein expression of a structural protein E-cadherin, and this was not observed in MCD-fed KO mice. Conclusions: FATP4 deficiency in an aP2-specific manner sensitized by MCD diet for increased hepatic fibrogenesis in part by the failure in upregulating cell-to-cell adhesion protein namely E-cadherin. Mechanism for this may involve FATP4 catalysis of specific phospholipids whereby lipidomics analyses of these liver samples are planned in our laboratory. Our results provide the first evidence for possible role of FATP4 in hepatic fibrogenesis, and further experiments using isolated hepatic stellate cells are necessary to verify this.

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Chamulitrat, Walee

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