Omega-3 polyunsaturated fatty acids protect human hepatoma cells from developing steatosis through FFA4 (GPR120)

• Published in: Biochimica et biophysica acta. Molecular and cell biology of lipids 2018-02, Vol.1863 (2), p.105-116
• Main Authors: Kang, Saeromi, Huang, Jin, Lee, Bo-Kyung, Jung, Young-Suk, Im, Eunok, Koh, Jung-Min, Im, Dong-Soon
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Calcium-Calmodulin-Dependent Protein Kinase Kinase - genetics; Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Docosahexaenoic acid; Docosahexaenoic Acids - pharmacology; Fatty Liver - genetics; Fatty Liver - metabolism; Fatty Liver - pathology; Fatty Liver - prevention & control; FFA4; Gene Knockdown Techniques; Hep G2 Cells; Hepatocytes; Humans; Hydrocarbons, Fluorinated - pharmacology; Liver; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Mice; Mice, Knockout; N-3 PUFA; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Steatosis; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Sulfonamides - pharmacology
• ISSN: 1388-1981; 1879-2618
• DOI: 10.1016/j.bbalip.2017.11.002

Protective effect of omega-3 polyunsaturated fatty acids (n-3 PUFA) on non-alcoholic fatty liver disease has been demonstrated. FFA4 (also known as GPR120; a G protein-coupled receptor) has been suggested to be a target of n-3 PUFA. FFA4 expression in hepatocytes has also been reported from liver biopsies in child fatty liver patients. In order to assess the functional role of FFA4 in hepatic steatosis, we used an in vitro model of liver X receptor (LXR)-mediated hepatocellular steatosis. FFA4 expression was confirmed in Hep3B and HepG2 human hepatoma cells. T0901317 (a specific LXR activator) induced lipid accumulation and docosahexaenoic acid (DHA; a representative n-3 PUFA) inhibited lipid accumulation. This DHA-induced inhibition was blunted by treatment of AH7614 (a FFA4 antagonist) and by transfection of FFA4 siRNA. SREBP-1c (a key transcription factor of lipogenesis) was induced by treatment with T0901317, and SREBP-1c induction was also inhibited by DHA at mRNA and protein levels. DHA-induced suppression of SREBP-1c expression was also blunted by FFA4-knockdown. Furthermore, DHA inhibited T0901317-induced lipid accumulation in primary hepatocytes from wild type mice, but not in those from FFA4 deficient mice. In addition, DHA-induced activations of Gq/11 proteins, CaMKK, and AMPK were found to be signaling components of the steatosis protective pathway. The results of this study suggest that n-3 PUFA protect hepatic steatosis by activating FFA4 in hepatocytes, and its signaling cascade sequentially involves FFA4, Gq/11 proteins, CaMKK, AMPK, and SREBP-1c suppression. [Display omitted] •n-3 PUFAs protected hepatic steatosis through FFA4/GPR120 in human and mouse hepatocytes.•Activation of FFA4 protected hepatic steatosis by suppressing SREBP-1c expression through AMPK.•n-3 PUFAs activation of FFA4 led to activation of Gq/11, CaMKK, AMPK, and suppression of SREBP-1c.