title: Impact of activating transcription factor 4 signaling on lipogenesis in HepG2 cells.
abstract: Non-alcoholic fatty liver disease (NAFLD) is a rapidly growing health threat that has previously been associated with lipogenesis. The direct effect of endoplasmic reticulum stress (ERS) inhibition on the induction of lipogenesis has not been investigated in hepatocytes in vitro. The impact of activating transcription factor‑4 (ATF4) on the lipogenic pathway and hepatic insulin transduction in liver cells also requires further investigation. In the present study, the triglyceride (TG) content of HepG2 cells stimulated with fructose was investigated using a commercially available enzymatic assay, and the expression levels of lipogenesis‑associated factors were determined by western blotting and reverse transcription‑quantitative polymerase chain reaction. Notably, the TG content of HepG2 cells was increased following incubation with fructose, which was accompanied by ERS. 4‑Phenylbutyric acid, an inhibitor of ERS, lowered the TG content by reducing the mRNA expression levels of sterol regulatory element‑binding protein 1 (SREBP‑1c) and carbohydrate‑responsive element‑binding protein (ChREBP), and the protein expression levels of fatty acid synthase (FAS), acetyl‑CoA carboxylase (ACC) and stearoyl‑CoA desaturase‑1 (SCD‑1). Conversely, tunicamycin, which is an inducer of ERS, increased the TG content and stimulated the expression of the above lipogeneic markers. ATF4 deficiency relieved TG accumulation and decreased the mRNA expression levels of SREBP‑1c and ChREBP, and protein expression levels of FAS, ACC and SCD‑1 in fructose‑treated HepG2 cells. Conversely, ATF4 overexpression increased the TG content by upregulating the mRNA expression levels of SREBP‑1c and ChREBP and protein expression levels of FAS, ACC and SCD‑1. Inhibition of ERS was shown to protect HepG2 cells against fructose‑induced TG accumulation, whereas induction of ERS stimulated hepatic lipogenesis. As a downstream transcription factor of the unfolded protein response, a deficiency in ATF4 attenuates fructose‑induced lipogenesis; while an overexpression of ATF4 can induce TG accumulation through stimulating hepatic lipogenesis. The results of the present study suggested that ATF4 may exert various physiological roles in lipid metabolism depending on the nutrient composition. In addition, these results suggested that ATF4 has a role in regulating lipogenesis and in the development of NAFLD; thus ATF4 may be considered a therapeutic target for NAFLD.
authors.affiliation: Department of Endocrinology and Metabolism, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China.
authors.forename: Lu-Ping
authors.initials: LP
authors.lastname: Ren
authors.affiliation: Department of Endocrinology and Metabolism, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China.
authors.forename: Xian
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Endocrinology and Metabolism, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China.
authors.forename: Guang-Yao
authors.initials: GY
authors.lastname: Song
authors.affiliation: Department of Endocrinology and Metabolism, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China.
authors.forename: Pu
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology and Metabolism, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Sun
authors.affiliation: Department of Endocrinology and Metabolism, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China.
authors.forename: Shu-Chun
authors.initials: SC
authors.lastname: Chen
authors.affiliation: Department of Nephrology, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China.
authors.forename: Zhi-Juan
authors.initials: ZJ
authors.lastname: Hu
authors.affiliation: Department of Endocrinology and Metabolism, Hebei General Hospital, Shijiazhuang, Hebei 050051, P.R. China.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Zhang
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005632:Fructose / Q000378:metabolism; D015870:Gene Expression; D020868:Gene Silencing; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D007328:Insulin; D008055:Lipids; D010654:Phenylbutyrates; D014415:Tunicamycin; D051701:Activating Transcription Factor 4; D005632:Fructose; C075773:4-phenylbutyric acid