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Metabolic Disorders II
Published in John F. Pohl, Christopher Jolley, Daniel Gelfond, Pediatric Gastroenterology, 2014
Fructose is a fruit sugar that naturally occurs in the body. Man-made fructose is used as a sweetener in many foods, including baby foods and drinks. After ingestion, fructose is degraded and phosphorylated to fructose-1-phosphate and then spliced by aldolase B (expressed in liver, kidneys, and small intestine) into dihydroxyacetone phosphate and D-glyceraldehyde. A deficiency of adolase B results in an accumulation of fructose-1-phosphate and trapping of phosphate. The downstream effects of aldolase B deficiency are the inhibition of glucose production and reduced generation of adenosine triphosphate. Figure 41.6 highlights the key deleterious effects of aldolase B deficiency.
Noninsulin-Dependent Animal Models of Diabetes Mellitus
Published in John H. McNeill, Experimental Models of Diabetes, 2018
Christopher H. S. McIntosh, Raymond A. Pederson
Genome scans and linkage analysis have identified MODY 3 as the most common form of MODY worldwide. The mutated gene was recently identified as the transcription factor hepatic nuclear factor (HNF)-1α,396 which is involved in the regulation of several hepatic genes. In pancreatic cells, it is a weak transactivator of the insulin-I gene. The mutated gene in MODY 1 was identified as HNF-4α, a member of the steroid/thyroid hormone superfamily that regulates expression of HNF-1α.397 Late-onset NIDDM appears in some family members who carry the mutation.11 Homozygous transgenic mice lacking HNF-lα did not thrive and died around the time of weaning.398 However, although they suffered from phenylketonurea and renal tubular dysfunction, they had normal blood glucose levels. The response to an intravenous glucose infusion appeared normal, but since there was a massive glycosuria any diabetic state may have been masked. It is not known how mutations in the HNF-1α and HNF-4α genes result in diabetes when present on a single allele. It was postulated that partial deficiency may lead to β-cell dysfunction and diabetes, or mutations may cause diabetes by acting in a dominant-negative fashion.396 HNF-4α acts on regulatory elements and promoters of a number of genes the products of which are involved in cholesterol, fatty acid, amino acid, and glucose metabolism.399 In transgenic studies, HNF-4α+/− mice did not have diabetes or abnormal glucose tolerance, however loss of both genes resulted in early embryonic death due to dysfunction of the visceral endoderm in which it is expressed,399 preventing studies on these animals. In vitro studies by Stoffel and Duncan399 showed that mutant (Gln268X (nonsense)) HNF-4α protein does not bind to DNA-binding site as a homodimer or heterodimer. Several genes involved in glucose uptake and glycolysis were shown to be dependent upon HNF-4α, including GLUT-2, aldolase B, and glyceraldehyde-3-phosphate dehydrogenase. Deficient expression of these proteins in β-cells probably accounts for the altered insulin secretion in patients with MODY. It was also found that levels of HNF-1α mRNA were only slightly reduced by the complete absence of HNF-4α. Therefore, other pathways are presumably also involved in patients with MODY 1.
Bioactive constituents of Salvia przewalskii and the molecular mechanism of its antihypoxia effects determined using quantitative proteomics
Published in Pharmaceutical Biology, 2020
Yafeng Wang, Delong Duo, Yingjun Yan, Rongyue He, Shengbiao Wang, Aixia Wang, Xinan Wu
Differential proteomic results showed the downregulation of Khk and Aldob, proteins related to fructose metabolism. Fructose is a natural monosaccharide broadly used in modern society. Fructose is absorbed via two major facilitative glucose transporters: GLUT5 and GLUT2 (Pan and Kong 2018). Fructose metabolism requires the coordinated action of 2 enzymes, ketohexokinase (Khk), which phosphorylates fructose to form fructose 1-phosphate (Fru1-P), and aldolase B, which splits Fru1-P into dihydroxyacetone phosphate and glyceraldehydes (Lanaspa et al. 2018), thereby producing substrates for fatty acid synthesis. Fructose bypasses glycolysis, and fructose is utilised much faster than glucose in de novo lipogenesis (Samuel 2011); thus, the excessive intake of fructose is closely associated with metabolic diseases such as diabetes and obesity (Walker and Goran 2015). Therefore, the repression of fructose-induced fatty liver is a key strategy for the prevention of these metabolic diseases. In this report, through the use of comparative proteomics, we demonstrate that SPM inhibited fructose metabolism via the downregulation of Khk and Aldob protein expression to prevent the lung injury associated with hypobaric hypoxia.
Hepatocellular carcinoma (HCC): the most promising therapeutic targets in the preclinical arena based on tumor biology characteristics
Published in Expert Opinion on Therapeutic Targets, 2021
Haichuan Wang, Xin Chen, Diego F. Calvisi
The PI3K/Akt-mTOR signaling pathway is a central regulator of HCC development. This signaling cascade includes various intracellular kinases, and among them, AKT is a prominent hub downstream of many RTKs. Upstream target proteins of AKT are stimuli-induced RTKs and include PI3K, phosphoinositide-dependent protein kinase (PDK), and mTOR complex 2 (mTORC2). Activated AKT enables the phosphorylation of downstream target proteins, including FOXO1, TSC1/2, and mTORC1 [53]. The use of AKT and mTOR inhibitors in HCC studies has been thoroughly reviewed elsewhere [54,55]. Although the applications of AKT and/or mTOR inhibitors showed an efficient tumor growth inhibition capacity in vitro and in vivo, the clinical trials so far conducted failed to reach compelling outcomes (Table 2). Current research efforts are devoted to generating more efficacious inhibitors targeting the PI3K/AKT-mTOR cascades and identifying biomarkers for patient selection as well as for combination therapies. The tuberous sclerosis complex (TSC) 1 and TSC2 are known as negative regulators of mTORC1 signaling. TSC1/2 is a GTPase-activating protein for the small GTPase Rheb, which is an essential activator of mTORC1. According to the TCGA cohort, ~4% of HCCs have TSC1 mutation, and ~5% of HCCs have TSC2 mutation. An independent study based on HBV-related HCCs documented ~16.8% of samples displaying TSC1 and/or TSC2 mutations. Of note, TSC2-mutant PDTXs are more sensitive to the treatment with the mTOR inhibitor rapamycin [56]. The PI3K/AKT/mTOR cascade is also involved in many metabolic processes in the liver, suggesting the modulation of the metabolism as an alternative therapeutic strategy against HCC. He et al. showed that loss of hepatic fructose-1, 6-bisphosphate aldolase B (Aldob) favors hepatocarcinogenesis by suppressing the interaction of AKT with its negative regulator protein phosphatase 2A (PP2A). Significantly, treatment with the PP2A activator SMAP inhibited HCC tumor growth in vitro, implying the relevance of AKT inhibition as an anti-neoplastic strategy in this tumor type [57].