Incorporation of exogenous lipids modulates insulin signaling in the hepatoma cell line, HepG2

The lipid content of cultured cells can be experimentally modified by suppl ementing the culture medium with specific lipids or by the use of phospholi pases. In the case of the insulin receptor, these methods have contributed to a better understanding of lipid disorder-related diseases. Previously, o ur laboratory demonstrated that experimental modification of the cellular l ipid composition of an insulin-sensitive rat hepatoma cell line (ZHC) resul ted in an alteration in insulin receptor binding and biological action (Bru neau et al., Biochim. Biophys, Acta 928 (1987) 287-296/297-304). In this pa per, we have examined the effects of lipid modification in another hepatoma cell line, HepG2. Exogenous linoleic acid (LA, n-6), eicosapentaenoic acid (EPA, n-3) or hemisuccinate of cholesterol (CHS) was added to HepG2 cells, to create a cellular model in which membrane composition was modified. In this model, we have shown that: (1) lipids were incorporated in treated Hep G2 cells, but redistributed differently when compared to treated ZHC cells; (2) that insulin signaling events, such as insulin receptor autophosphoryl ation and the phosphorylation of the major insulin receptor substrate (IRS- 1) were altered in response to the addition of membrane lipids or cholester ol derived components; and (3) different lipids affected insulin receptor s ignaling differently. We have also shown that the loss of insulin receptor autophosphorylation in CHS-treated cells can be correlated with a decreased sensitivity to insulin. Overall, the results suggest that the lipid enviro nment of the insulin receptor may play an important role in insulin signal transduction. (C) 1999 Elsevier Science B.V. All rights reserved.