Longo, M.; Paolini, E.; Meroni, M.; Duca, L.; Motta, I.; Fracanzani, A.L.; Di Pierro, E.; Dongiovanni, P. α-Lipoic Acid Improves Hepatic Metabolic Dysfunctions in Acute Intermittent Porphyria: A Proof-of-Concept Study. Diagnostics2021, 11, 1628.
Longo, M.; Paolini, E.; Meroni, M.; Duca, L.; Motta, I.; Fracanzani, A.L.; Di Pierro, E.; Dongiovanni, P. α-Lipoic Acid Improves Hepatic Metabolic Dysfunctions in Acute Intermittent Porphyria: A Proof-of-Concept Study. Diagnostics 2021, 11, 1628.
Background: Acute intermittent porphyria (AIP) is caused by haploinsufficiency of porphobilin-ogen deaminase (PBGD) enzymatic activity. Acute attacks occur in response to fasting and altera-tions 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, the α-lipoic acid (α-LA) as a potential therapeutic strategy. Methods: HepG2 cells were transfected with a siRNA targeting PBGD (siPBGD). Cells were cul-tured with low glucose concentration to mimic fasting and exposed to α-LA alone or with glu-cose. Results: At baseline, siPBGD cells showed lower expression of genes involved in glycolysis and mitochondrial dynamics along with reduced total ATP levels. Fasting further unbalanced gly-colysis by inducing ATP shortage in siPBGD cells and activated DRP1, which mediates mito-chondrial separation. Consistently, siPBGD cells in fasted state showed the lowest protein levels of Complex IV which belong to the oxidative phosphorylation (OXPHOS) machinery. α-LA up-regulated glycolysis and prompted ATP synthesis and triglyceride secretion, thus possibly providing energy fuels to siPBGD cells by improving glucose utilization. Finally, siPBGD exposed to α-LA plus glucose raised mitochondrial dynamics, OXPHOS activity and energy production. Conclusions: α-LA-based therapy may ameliorate glucose metabolism and mitochondrial dys-functions in siPBGD hepatocytes. Keywords: AIP, PBGD, glucose metabolism, mitobiogenesis, α-lipoic acid
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.