Journal Article

(+)-Lipoic acid reduces mitochondrial unfolded protein response and attenuates oxidative stress and aging in an in vitro model of non-alcoholic fatty liver disease

Orlando, Laura, Denaro, Simona, Alanazi, Amer M., Musso, Nicolò, Salomone, Federico, Li Volti, Giovanni, Amorini, Angela Maria, Lazzarino, Giacomo, Lazzarino, Giuseppe, Longhitano, Lucia, Bonacci, Paolo, Torella, Daniele, Tibullo, Daniele, Tropea, Emanuela, Bramanti, Vincenzo, Nicolosi, Anna, Distefano, Alfio, Giallongo, Sebastiano, Ferrigno, Jessica, Barbagallo, Ignazio Alberto

2024

Overview

Background Non-alcoholic fatty liver disease (NAFLD) is a liver disorder characterized by the ac-cumulation of fat in hepatocytes without alcohol consumption. Mitochondrial dysfunction and endoplasmic reticulum (ER) stress play significant roles in NAFLD pathogenesis. The unfolded protein response in mitochondria (UPRmt) is an adaptive mechanism that aims to restore mitochondrial protein homeostasis and mitigate cellular stress. This study aimed to investigate the effects of ( +)-Lipoic acid (ALA) on UPRmt, inflammation, and oxidative stress in an in vitro model of NAFLD using HepG2 cells treated with palmitic acid and oleic acid to induce steatosis. Results Treatment with palmitic and oleic acids increased UPRmt-related proteins HSP90 and HSP60 (heat shock protein), and decreased CLPP (caseinolytic protease P), indicating ER stress activation. ALA treatment at 1 μM and 5 μM restored UPRmt-related protein levels. PA:OA (palmitic acid:oleic acid)-induced ER stress markers IRE1α (Inositol requiring enzyme-1), CHOP (C/EBP Homologous Protein), BIP (Binding Immunoglobulin Protein), and BAX (Bcl-2-associated X protein) were significantly reduced by ALA treatment. ALA also enhanced ER-mediated protein glycosylation and reduced oxidative stress, as evidenced by decreased GPX1 (Glutathione peroxidase 1), GSTP1 (glutathione S-transferase pi 1), and GSR (glutathione-disulfide reductase) expression and increased GSH (Glutathione) levels, and improved cellular senescence as shown by the markers β-galactosidase, γH2Ax and Klotho-beta. Conclusions In conclusion, ALA ameliorated ER stress, oxidative stress, and inflammation in HepG2 cells treated with palmitic and oleic acids, potentially offering therapeutic benefits for NAFLD providing a possible biochemical mechanism underlying ALA beneficial effects. Graphical Abstract

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acids / Aging / Analysis / Antibodies / BAX protein / Bcl-2 protein / Bcl-x protein / Biomedical and Life Sciences / Biomedicine / Care and treatment / CCAAT/enhancer-binding protein / Cell culture / Cellular Senescence / Diagnosis / Disulfide reductase / Endoplasmic reticulum / Endoplasmic Reticulum Stress / Endoribonucleases - metabolism / Fatty liver / Genes / Genomics / Glutathione peroxidase / Glutathione transferase / Glycosylation / Health aspects / Heat / Heat shock proteins / Hepatocytes / Hepatocytes - pathology / Homeostasis / Hsp60 protein / Hsp90 protein / Humans / Inflammation / Inflammation - pathology / Inositol / Klotho protein / Lipoic acid / Liver - pathology / Liver diseases / Medicine/Public Health / Membranes / Metabolism / Mitochondria / Mitochondrial dysfunction / Non-alcoholic fatty liver disease / Non-alcoholic Fatty Liver Disease - pathology / Oleic acid / Oleic Acid - metabolism / Oleic Acid - pharmacology / Oxidative Stress / Palmitic acid / Palmitic Acid - metabolism / Palmitic Acid - pharmacology / Palmitic Acids - metabolism / Palmitic Acids - pharmacology / Protein folding / Protein Serine-Threonine Kinases - metabolism / Quality control / Reagents / Risk factors / Senescence / Thioctic Acid - metabolism / Thioctic Acid - pharmacology / Thioctic Acid - therapeutic use / Translational Signaling and System Biology / Unfolded protein re-sponse / Unfolded Protein Response