$\upalpha$-Lipoic Acid Improves Hepatic Metabolic Dysfunctions in Acute Intermittent Porphyria: A Proof-of-Concept Study [alpha-Lipoic Acid Improves Hepatic Metabolic Dysfunctions in Acute Intermittent Porphyria: A Proof-of-Concept Study]

Background: Acute intermittent porphyria (AIP) is caused by the haploinsufficiency of porphobilinogen deaminase (PBGD) enzymatic activity. Acute attacks occur in response to fasting, and alterations in glucose metabolism, insulin resistance, and mitochondrial turnover may be involved in AIP pathophysiology. Therefore, we investigated the metabolic pathways in PBGD-silenced hepatocytes and assessed the efficacy of an insulin mimic, alpha-lipoic acid (alpha-LA), as a potential therapeutic strategy. Methods: HepG2 cells were transfected with siRNA-targeting PBGD (siPBGD). Cells were cultured with low glucose concentration to mimic fasting and exposed to alpha-LA alone or with glucose. Results: At baseline, siPBGD cells showed a lower expression of genes involved in glycolysis and mitochondrial dynamics along with reduced total ATP levels. Fasting further unbalanced glycolysis by inducing ATP shortage in siPBGD cells and activated DRP1, which mediates mitochondrial separation. Consistently, siPBGD cells in the fasted state showed the lowest protein levels of Complex IV, which belongs to the oxidative phosphorylation (OXPHOS) machinery. alpha-LA upregulated glycolysis and prompted ATP synthesis and triglyceride secretion, thus possibly providing energy fuels to siPBGD cells by improving glucose utilization. Finally, siPBGD exposed to alpha-LA plus glucose raised mitochondrial dynamics, OXPHOS activity, and energy production. Conclusions: alpha-LA-based therapy may ameliorate glucose metabolism and mitochondrial dysfunctions in siPBGD hepatocytes.