Atorvastatin-Curcuminoids Co-Treatment Suppresses ApoB Secretion and Alters Lipid and Glucose Homeostasis in HuH-7 Cells

Background/Objectives: Although statins are still the main treatment for dyslipidemia, differences in patient responses, residual cardiovascular risk, and treatment side effects highlight the need for additional methods. Curcumin has attracted considerable interest because of its reported cardioprotective and lipid- and glucose-modulating effects, as well as its ability to influence cellular stress and survival pathways, highlighting its potential relevance to cardiovascular and metabolic disease. This study investigated the effects of atorvastatin (ATO), curcuminoid extract (CUR), and their combination on lipid and glucose metabolism and cell fate in hepatocellular carcinoma-derived cell lines. Methods: Huh-7 cells were treated for 48 h with ATO (10 μM), CUR (20 μM), or their combination (MIX). MTT assays characterized concentration-dependent cytotoxicity and informed concentration selection, and CellTiter-Glo assessed cell viability. ApoB expression and secretion were evaluated by Western blot and ELISA. Lipid accumulation was assessed by Oil Red O microscopy and quantitative analysis. Glucose uptake was measured before and after insulin challenge. Additionally, expression of relevant genes regulating cholesterol, lipoprotein, and glucose metabolism was assessed by qPCR, and apoptosis was examined by Annexin V/PI flow cytometry and Western blotting for apoptotic markers. Results: The ATO-curcuminoid combination markedly reduced ApoB expression and secretion compared with control (p < 0.01). In contrast, the combination significantly increased intracellular lipid accumulation compared with control, ATO, and CUR (p < 0.001). Additionally, CUR and the ATO-curcuminoid combination significantly reduced glucose uptake before and after insulin challenge (p < 0.01; p < 0.001, respectively). Consistent with the impaired glucose uptake, the ATO-curcuminoid combination significantly reduced GLUT2 protein expression compared with control and ATO (p < 0.05 and p < 0.01, respectively). The ATO-curcuminoid combination also significantly increased early and late apoptosis and reduced viable-cell populations (p < 0.05; p < 0.01, respectively). Molecular docking and molecular dynamics simulations revealed that curcuminoids occupied the catalytic domain of HMG-CoA reductase and maintained conserved interactions with key residues, including GLY656, ASN658, and GLY808. Conclusions: ATO-curcuminoid co-treatment suppressed ApoB secretion but was accompanied by increased intracellular lipid accumulation, altered glucose uptake and GLUT2 expression, and apoptosis, indicating a discordant hepatic response. Computational analyses suggested potential interactions between curcuminoids and the catalytic region of HMG-CoA reductase; however, these findings are hypothesis-generating and require direct enzyme-inhibition and kinetic validation.