Exendin-4-induced reduction of steatosis in HepG2 cells implicates upregulation of essential lipid metabolism genes via modulation of MALAT1

Background The favorable effect of the glucagon-like peptide-1 receptor agonist (GLP-1RA) Exendin-4 (Ex-4) on steatosis induced by fatty acids such as oleic acid (OA) in HepG2 cells is characterized by the modulation of the expression of several long-non-coding RNAs, notably downregulating MALAT1. This in vitro study delves into the intricacies of MALAT1 involvement in the observed amelioration of OA-induced steatosis under the influence of Ex-4. Methods We established steatotic HepG2 cells by treating them with oleic acid (OA). Reduction of steatosis was induced by the treatment of steatotic cells with Ex-4, and gene expression was quantified using total RNA. HepG2 cells were transfected with short interfering RNAs (siRNAs) using lipofectamine RNAiMAX to induce the silencing of MALAT1. Results Exposure of HepG2 cells to 200nM of Ex-4 for 3h led to a significant reduction in lipid accumulation induced by OA stimulation. OA treatment resulted in a significant upregulation of essential lipid metabolism-related genes, SREBP-1, PPARγ, SCD1, FAS, ACC, DGAT1, DGTA2, CPT1A, MTTP, NR1H2, and CD36, with a concurrent downregulation of ACADL expression. The presence of Ex-4, in addition to OA, significantly mitigated the upregulation of SREBP-1, PPARγ, DGAT1, DGAT2, SCD1, ACC, and NR1H2. Interestingly, Ex-4 further increased CD36 expression, while it did not significantly affect the expression levels of FAS, ACADL, CPT1A, and MTTP. The silencing of MALAT1 expression had no significant impact on the expression levels of SREBP-1 and PPARγ observed in response to OA and Ex-4 treatment. However, it exerted varying degrees of influence on the expression of other genes. Remarkably, MALAT1 suppression robustly counteracted the exacerbated increase in CD36 expression induced by Ex-4. Conclusions Our study suggests that the beneficial effect of Ex-4 on steatosis could partially result from the downregulation of MALAT1, which in turn regulates several lipid metabolism genes, especially downregulation of CD36 and subsequent reduction of. Further functional investigations are warranted to confirm these findings in in vivo models of hepatic steatosis.