Dietary fatty acids activate FATP4 and lipid transport via HIF1α and KDM4B in the small intestinal enterocytes.

The intestinal lipid metabolism is a vital factor that affects energy homeostasis. However, the regulatory mechanisms of the intestinal lipid transport and absorption, which is the first step of intestinal lipid metabolism, remain unclear. In this study, we found that high-fat diet increased the expression of fatty acid transporter protein 4 (FATP4) and KDM4B in the small intestines of both male and female mice. In the enterocytes, fatty acids (palmitic acid and oleic acid) increased the expression of KDM4B and FATP4 dose- and time-dependently. Knockdown of KDM4B inhibited the fatty acids induced elevation of FATP4 and lipid absorption in the enterocytes. Meanwhile, our results showed that the HIF1α was increased by fatty acids in the small intestines and enterocytes, and the inhibition of HIF1α blocked the fatty acid-induced increase of KDM4B as well as FATP4 and lipid absorption. In summary, dietary fatty acids regulated FATP4 and lipid absorption in the small intestinal enterocytes via HIF1α and KDM4B. These findings provide insights into the regulatory mechanisms of intestinal lipid absorption and potential therapeutic targets to combat metabolic diseases such as obesity.