Nutrients and Porphyria: An Intriguing Crosstalk

Pierro, Elena Di; Granata, Francesca

doi:10.3390/ijms21103462

Cited by 24 publications

(18 citation statements)

References 108 publications

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“…However, the downregulation of glycolysis and the biochemical evaluation of energetic status of siPBGD cells could, in broad terms, mirror the energy failure featuring AIP patients at higher risk of developing symptoms [ 12 , 24 , 25 , 26 ]. Previous evidence has outlined that most of the dysregulated pathways in the liver that may precipitate in the AIP acute attacks are under the transcriptional regulation of PCG1α, a powerful nutrient sensor activated in response to stressful factors [ 27 ]. In the AIP context, it attempted to re-establish glucose homeostasis by activating hepatic gluconeogenesis and increasing mitochondrial mass, but it also induced ALAS1 expression [ 12 , 13 , 17 ], thereby exacerbating the porphyrins’ overproduction.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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, α-lipoic acid (α-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 α-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. α-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 α-LA plus glucose raised mitochondrial dynamics, OXPHOS activity, and energy production. Conclusions: α-LA-based therapy may ameliorate glucose metabolism and mitochondrial dysfunctions in siPBGD hepatocytes.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…Previous evidence has outlined that most dysregulated pathways in the liver which may precipitate the AIP acute attacks are under the transcriptional regulation of PCG1α, a powerful nutrient sensor activated in response to stressful factors [28]. In AIP context, PGC1α attempted to re-establish glucose homeostasis by activating hepatic gluconeogenesis and increasing mitochondrial mass, but it also induced ALAS1 expression [12,13,17], thereby exacerbating the porphyrins 'overproduction.…”

Section: Discussionmentioning

confidence: 99%

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

Longo¹,

Paolini²,

Meroni³

et al. 2021

Preprint

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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

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“…The study was performed with an overall minimal increase in the mean exposure time per day, and the same authors evaluated the results to be clinically irrelevant. A drawback of using β-carotene is that its dosage should not exceed 25 mg/day, as higher dosages entail an increased risk of lung and stomach cancer [ 82 ]. More effective therapy in inducing skin pigmentation is based on the stimulation of melanocytes by UV radiation [ 15 ].…”

Section: Managementmentioning

confidence: 99%

Recognized and Emerging Features of Erythropoietic and X-Linked Protoporphyria

et al. 2022

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Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inherited disorders resulting from defects in two different enzymes of the heme biosynthetic pathway, i.e., ferrochelatase (FECH) and delta-aminolevulinic acid synthase-2 (ALAS2), respectively. The ubiquitous FECH catalyzes the insertion of iron into the protoporphyrin ring to generate the final product, heme. After hemoglobinization, FECH can utilize other metals like zinc to bind the remainder of the protoporphyrin molecules, leading to the formation of zinc protoporphyrin. Therefore, FECH deficiency in EPP limits the formation of both heme and zinc protoporphyrin molecules. The erythroid-specific ALAS2 catalyses the synthesis of delta-aminolevulinic acid (ALA), from the union of glycine and succinyl-coenzyme A, in the first step of the pathway in the erythron. In XLP, ALAS2 activity increases, resulting in the amplified formation of ALA, and iron becomes the rate-limiting factor for heme synthesis in the erythroid tissue. Both EPP and XLP lead to the systemic accumulation of protoporphyrin IX (PPIX) in blood, erythrocytes, and tissues causing the major symptom of cutaneous photosensitivity and several other less recognized signs that need to be considered. Although significant advances have been made in our understanding of EPP and XLP in recent years, a complete understanding of the factors governing the variability in clinical expression and the severity (progression) of the disease remains elusive. The present review provides an overview of both well-established facts and the latest findings regarding these rare diseases.

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Nutrients and Porphyria: An Intriguing Crosstalk

Cited by 24 publications

References 108 publications

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

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

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

Recognized and Emerging Features of Erythropoietic and X-Linked Protoporphyria

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