Preprint Communication Version 1 Preserved in Portico This version is not peer-reviewed

The α-Lipoic Acid Improves Hepatic Metabolic Dysfunctions in Acute Intermittent Porphyria: A Proof-of-Concept Study

Version 1 : Received: 3 August 2021 / Approved: 4 August 2021 / Online: 4 August 2021 (14:45:07 CEST)

A peer-reviewed article of this Preprint also exists.

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. 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.

Journal reference: Diagnostics 2021, 11, 1628
DOI: 10.3390/diagnostics11091628

Abstract

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

Keywords

AIP; PBGD; glucose metabolism; mitobiogenesis; alpha-lipoic acid

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