Fumarylacetoacetate hydrolase gene as a knockout target for hepatic chimerism and donor liver production

Larson, Ellen L.; Joo, Dong Jin; Nelson, Erek; Amiot, Bruce; Aravalli, Rajagopal N.; Nyberg, Scott L.

doi:10.1016/j.stemcr.2021.09.018

Cited by 5 publications

(3 citation statements)

References 104 publications

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“…Fumaryl acetoacetic acid hydrolase (FAH) is responsible for the final step of tyrosine metabolism. Reduced expression of fah leads to accumulation of the toxic metabolite fumaracetic acid (FAA) in hepatocytes and proximal renal tubules, leading to mutation and apoptosis [ 77 ]. In this experiment, fah expression levels were significantly reduced in the R64 diet group, suggesting that LCSM substitution for FM may cause apoptosis in S. sihama hepatocytes, as corroborated by H&E sections of the liver.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Analysis of Liver in Silver sillago, Sillago sihama Fed with High-Level Low-Gossypol Cottonseed Meal in Replacement of Fishmeal Diet

Líu

Zhou

Dong

et al. 2023

Animals

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Understanding the molecular mechanisms involved in adaptation to alternate diets has become a significant concern, as increasing amounts of fishmeal (FM) protein in aquafeeds are being substituted with plant protein. Thus, the goal of this study was to assess growth performance, quality, and liver function of juvenile Sillago sihama (S. sihama) through growth indices, whole-body composition, histology of the liver, and RNA-sequencing (RNA-seq), after they were fed a formulated diet with 64% low-gossypol cottonseed meal (LCSM) for 56 days, compared to those fed a traditional FM-based diet. Indicators of growth, including final body weight (FBW), weight gain rate (WGR), specific growth rate (SGR), protein efficiency ratio (PER), and condition factor (CF), were considerably lower in the 64% LCSM (R64) group than in the FM diet group. In the R64 diet, the whole crude lipid was significantly lower than in the FM diet. The hematoxylin–eosin section showed that dietary high levels of LCSM resulted in diffuse lipid vacuolation in the liver of S. sihama. According to a liver transcriptome analysis, high LCSM intake in the diet significantly impacted lipid synthesis and catabolism, elevated pathways for cholesterol synthesis, blocked several amino acid metabolic pathways, and adversely affected hepatic gluconeogenesis and glycolysis. The findings of this study indicate that feeding high levels of LCSM in S. sihama is harmful to the growth of the organism and can harm the liver’s structural integrity, as well as obstruct the normal metabolism of amino acids, lipids, and carbohydrates. Therefore, it is not recommended to substitute LCSM for high levels of FM in the diet of S. sihama.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic Analysis of Liver in Silver sillago, Sillago sihama Fed with High-Level Low-Gossypol Cottonseed Meal in Replacement of Fishmeal Diet

Líu

Zhou

Dong

et al. 2023

Animals

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“…Investigators in the UK are also exploring the potential for cell-based therapies such as allogeneic human macrophages to enhance liver regeneration and recovery in patients with APAP overdose 159,160 . Alternately, stem cell expansion may be accomplished through production of chimeric humanized animals (eg, pigs) 161,162 …”

Section: Alf Managementmentioning

confidence: 99%

“… 159 , 160 Alternately, stem cell expansion may be accomplished through production of chimeric humanized animals (eg, pigs). 161 , 162 …”

Section: Alf Managementmentioning

confidence: 99%

Future directions in acute liver failure

Stravitz¹,

Fontana²,

Karvellas³

et al. 2023

Hepatology

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Acute liver failure (ALF) describes a clinical syndrome of rapid hepatocyte injury leading to liver failure manifested by coagulopathy and encephalopathy in the absence of pre-existing cirrhosis. The hallmark diagnostic features are a prolonged prothrombin time (ie, an international normalized ratio of prothrombin time of ≥1.5) and any degree of mental status alteration (HE). As a rare, orphan disease, it seemed an obvious target for a multicenter network. The Acute Liver Failure Study Group (ALFSG) began in 1997 to more thoroughly study and understand the causes, natural history, and management of ALF. Over the course of 22 years, 3364 adult patients were enrolled in the study registry (2614 ALF and 857 acute liver injury—international normalized ratio 2.0 but no encephalopathy—ALI) and >150,000 biosamples collected, including serum, plasma, urine, DNA, and liver tissue. Within the Registry study sites, 4 prospective substudies were conducted and published, 2 interventional (N-acetylcysteine and ornithine phenylacetate), 1 prognostic [13C-methacetin breath test (MBT)], and 1 mechanistic (rotational thromboelastometry). To review ALFSG’s accomplishments and consider next steps, a 2-day in-person conference was held at UT Southwestern Medical Center, Dallas, TX, entitled “Acute Liver Failure: Science and Practice,” in May 2022. To summarize the important findings in the field, this review highlights the current state of understanding of ALF and, more importantly, asks what further studies are needed to improve our understanding of the pathogenesis, natural history, and management of this unique and dramatic condition.

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