Lipid droplet formation in response to oleic acid in Huh-7 cells is a fatty acid receptor mediated event

Abstract

BSTRACTIt is unclear how changes in lipid droplet size and number are regulated -for example, it is not known whether this involves a signalling pathway or is directed by cellular lipid uptake. Here, we show that oleic acid stimulates lipid droplet formation by activating the long-chain fatty acid receptor FFAR4, which signals through a pertussis-toxin-sensitive G-protein signalling pathway involving phosphoinositide 3-kinase (PI3-kinase), AKT (also known as protein kinase B) and phospholipase D (PLD) activities. This initial lipid droplet formation is not dependent upon exogenous lipid, whereas the subsequent more sustained increase in the number of lipid droplets is dependent upon lipid uptake. These two mechanisms of lipid droplet formation point to distinct potential intervention points.

The anti-tumor drug 2-hydroxyoleic acid (Minerval) stimulates signaling and retrograde transport

“…In breast cancer cells, OA was shown to stimulate proliferation [20, 41], and to rapidly increase cytosolic Ca 2+ and activate PI3K and AKT1 [41]. PI3K and AKT1 were also activated by OA in the hepatoma cell line Huh-7 [42]. Both in the above studies and in our experiments, the fatty acids OA and OHOA appear to act as growth factors.…”

“…In a similar manner, OA was shown to induce proliferation and MAPK1/3 activity in MCF-7 cells via transactivation of the EGFR, possibly after initial stimulation of the FFAR1/4 [20]. Moreover, OA was found to stimulate PI3K and AKT1 via FFAR4 in Huh-7 cells [42]. It remains to be seen whether the OHOA-induced signaling might be mediated via members of this class of receptors.…”

FFA4 receptor (GPR120): A hot target for the development of anti-diabetic therapies

“…The activation of FFA4 receptor stimulated lipid droplet formation, which was blocked by the G αi inhibitor, PTX, and PI3K inhibitor, LY294002 (Rohwedder et al, 2014); however, there is no direct biochemical evidence for FFA4 receptor-G αi coupling. Whether activated FFA4 receptor could signal through G αi or other G α subtypes in different tissues or cells awaits more research.…”

“…In addition to the functions of FFA4 receptor in the adipose tissue, macrophages, endocrine cells and taste buds, the activation of FFA4 receptor was found to regulate lipid droplet formation in Huh-7 cells (Rohwedder et al, 2014), promote angiogenesis through G αq -dependent signaling and cell survival and induce anti-apoptotic effects in a number of cell lines Wu et al, 2013). Considering the wide distribution of FFA4 receptor in many tissues, the discovery of more FFA4 receptor functions is expected.…”

Hepatitis C Virus Selectively Alters the Intracellular Localization of Desmosterol

“…To examine this possibility, we induced LD formation in uninfected Huh7.5 cells via an independent mechanism. Oleic acid activates a signalling cascade involving phosphoinositide 3-kinase, AKT, and phospholipase D. This leads to incorporation of endogenous lipids into LDs, induction of triglyceride synthesis, and incorporation of oleic acid itself into LDs 26 . Nile red staining of uninfected Huh7.5 cells treated with exogenous desmosterol revealed disperse staining (Fig.…”