Cobalt chloride induces the reduction of fibroblast growth factor 21 in Caco‐2 cells through HIF and PPAR‐α and –γ pathway

Abstract

Fibroblast growth factor 21 (FGF21) has emerged as an important metabolic regulator of glucose and lipid metabolism. Previously, FGF21 present in the adipose tissue regulates lipolysis, and in the liver increases fatty acid oxidation. FGF21 also is present in the intestine. Little is known about FGF21 in intestine. Intestinal epithelial cells are positioned between an anaerobic lumen and a highly metabolic lamina propria, which has a steep physiologic oxygen gradient. Physiological and pathological hypoxia induces the hypoxia‐inducible factors (HIF). We evaluated how the hypoxic state regulates FGF21 in intestine‐like Caco‐2 cells. Caco‐2 cells were treated with cobalt chloride, a chemical hypoxia mimetic. Cobalt chloride treatment decreased mRNA levels of FGF21, but increased mRNA levels of Glut‐1, a glucose transporter transcriptionally regulated by HIF, in a time dependent manner. Inhibition of HIF and transfection of a dominant negative HIF‐1α plasmid eliminated this effect. Further studies showed that cobalt chloride treatment reduced the mRNA levels of PPAR‐α and –γ, of which HIF is a negative regulator. In addition, cobalt chloride treatment decreases the mRNA levels of FGF21 in mouse colon. Hypoxia reduced FGF21 is, at least in part, mediated via HIF and PPAR–α and –γ pathway. Further study is needed to determine the intestinal metabolic change regulated by FGF‐21 under hypoxic conditions.