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Abstract
Acute hepatic porphyrias are rare metabolic liver disorders characterized by impaired heme biosynthesis, leading to accumulation of toxic porphyrin intermediates, oxidative stress, mitochondrial dysfunction, and liver injury. Current therapies are limited by cost, efficacy, and safety concerns, emphasizing the need for novel treatment strategies. Prior work showed that hepatocyte-specific deletion of β-catenin reduced DDC-induced porphyrin accumulation, protein aggregation, and liver Acute hepatic porphyrias are rare metabolic liver disorders characterized by impaired heme biosynthesis, leading to accumulation of toxic porphyrin intermediates, oxidative stress, mitochondrial dysfunction, and liver injury. Current therapies are limited by cost, efficacy, and safety concerns, emphasizing the need for novel treatment strategies. Prior work showed that hepatocyte-specific deletion of β-catenin reduced DDC-induced porphyrin accumulation, protein aggregation, and liver injury; however, the interplay between Wnt signaling, its target glutamine synthetase (GS), and hepatic autophagy remains poorly understood.
This dissertation investigates how Wnt signaling and GS regulate hepatic porphyrin metabolism, autophagy, and mitochondrial quality control during xenobiotic-induced porphyric liver injury. Using a combination of spatial transcriptomics, targeted metabolomics, confocal imaging, high-resolution respirometry, and transmission electron microscopy, and traditional molecular biology techniques, we demonstrate that Wnt/GS signaling coordinates transcriptional, metabolic, and organelle-level responses to porphyric injury. Loss of Wnt signaling suppressed DDC-induced activation of porphyrin biosynthesis genes, normalized porphyrin intermediate accumulation, and enhanced autophagic flux. GS deletion similarly suppressed porphyrin biosynthesis, primarily by limiting intracellular glutamine availability, a critical substrate for heme production. Combined Wnt inhibition and GS deletion further amplified autophagy and reduced porphyrin accumulation, establishing distinct but complementary roles for these pathways in hepatic homeostasis.
Additionally, Wnt inhibition restored mitophagy during DDC-induced hepatic injury, whereas GS deletion primarily modulated mitochondrial respiration. This work proposes that persistent Wnt activation during injury promotes mitochondrial biogenesis while suppressing mitophagic clearance, exacerbating organelle dysfunction. Loss of Wnt signaling alleviates this constraint, improving mitochondrial quality control and metabolic resilience, supported by our prior findings that β-catenin deletion enhances autophagy and by current literature indicating a bidirectional relationship between Wnt/β-catenin signaling and autophagy/mitophagy.
Together, these findings define a Wnt–GS–autophagy axis that regulates hepatic adaptation to porphyric injury through coordinated control of heme biosynthesis, autophagy, mitochondrial turnover, and bioenergetic function. Additionally, Wnt and GS deficiency reprogram Kupffer cells toward a reparative, debris-clearing phenotype, limiting fibrogenic progression during porphyric injury. Therapeutic modulation of this axis may represent a novel strategy to restore hepatic homeostasis and mitigate metabolic liver disease.