Early PQQ supplementation has persistent long‐term protective effects on developmental programming of hepatic lipotoxicity and inflammation in obese mice

Jonscher, Karen R.; Stewart, Michael S.; Alfonso-García, Alba; DeFelice, Brian C.; Wang, Xiaoxin X.; Luo, Yuhuan; Levi, Moshe; Heerwagen, Margaret J. R.; Janssen, Rachel C.; Houssaye, Becky A. de la; Wiitala, Ellen; Florey, Garrett M.; Jonscher, Raleigh; Potma, Eric O.; Fiehn, Oliver; Friedman, Jacob E.

doi:10.1096/fj.201600906r

Cited by 48 publications

(60 citation statements)

References 72 publications

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“…WD accelerates steatosis and mild fibrosis and at 20 weeks of age recapitulates a phenotype similar to human NASH; therefore, we used a similar formulation in our studies. Sibling C57BL/6J mice were randomly stratified into breeding groups and fed either standard chow (CH, 2019; Envigo, Indianapolis, IN) or WD (TD.88137; Envigo) ad libitum with or without BioPQQ supplementation in their drinking water (3.8 μM), as described . Di‐sodiated PQQ (BioPQQ) was generously provided to K. R. J. as a gift by the Mitsubishi Gas and Chemical Company.…”

Section: Methodsmentioning

confidence: 99%

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Pyrroloquinoline quinone prevents developmental programming of microbial dysbiosis and macrophage polarization to attenuate liver fibrosis in offspring of obese mice

Friedman¹,

Dobrinskikh

Alfonso-García

et al. 2018

Hepatology Communications

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Increasingly, evidence suggests that exposure to maternal obesity creates an inflammatory environment in utero, exerting long‐lasting postnatal signatures on the juvenile innate immune system and microbiome that may predispose offspring to development of fatty liver disease. We found that exposure to a maternal Western‐style diet (WD) accelerated fibrogenesis in the liver of offspring and was associated with early recruitment of proinflammatory macrophages at 8‐12 weeks and microbial dysbiosis as early as 3 weeks of age. We further demonstrated that bone marrow‐derived macrophages (BMDMs) were polarized toward an inflammatory state at 8 weeks of age and that a potent antioxidant, pyrroloquinoline quinone (PQQ), reversed BMDM metabolic reprogramming from glycolytic toward oxidative metabolism by restoring trichloroacetic acid cycle function at isocitrate dehydrogenase. This resulted in reduced inflammation and inhibited collagen fibril formation in the liver at 20 weeks of age, even when PQQ was withdrawn at 3 weeks of age. Beginning at 3 weeks of age, WD‐fed mice developed a decreased abundance of Parabacteroides and Lactobacillus, together with increased Ruminococcus and decreased tight junction gene expression by 20 weeks, whereas microbiota of mice exposed to PQQ retained compositional stability with age, which was associated with improved liver health. Conclusion: Exposure to a maternal WD induces early gut dysbiosis and disrupts intestinal tight junctions, resulting in BMDM polarization and induction of proinflammatory and profibrotic programs in the offspring that persist into adulthood. Disrupted macrophage and microbiota function can be attenuated by short‐term maternal treatment with PQQ prior to weaning, suggesting that reshaping the early gut microbiota in combination with reprogramming macrophages during early weaning may alleviate the sustained proinflammatory environment, preventing the rapid progression of nonalcoholic fatty liver disease to nonalcoholic steatohepatitis in offspring of obese mothers. (Hepatology Communications 2018;2:313‐328)

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Section: Methodsmentioning

confidence: 99%

“…Serum was collected and stored as described . Aspartate aminotransferase (AST), alanine aminotransferase (ALT), cholesterol, and triglycerides were measured using standardized protocols by the University of Colorado Anschutz Department of Laboratory Services clinical laboratory.…”

Section: Methodsmentioning

confidence: 99%

Pyrroloquinoline quinone prevents developmental programming of microbial dysbiosis and macrophage polarization to attenuate liver fibrosis in offspring of obese mice

Friedman¹,

Dobrinskikh

Alfonso-García

et al. 2018

Hepatology Communications

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“…Neither metformin nor probiotic use in nondiabetic obese pregnant women were effective in lowering offspring weight. However, pyrroloquinoline quinone (a natural antioxidant with a beneficial effect on lipid metabolism and glycemic control) and methyl donors (choline, betaine, vitamin B12, and folic acid) were beneficial in murine NASH …”

Section: Nafldmentioning

confidence: 99%

“…However, pyrroloquinoline quinone (a natural antioxidant with a beneficial effect on lipid metabolism and glycemic control) and methyl donors (choline, betaine, vitamin B12, and folic acid) were beneficial in murine NASH. (44) AFLP AFLP is an uncommon (1:7,000-15,000) and potentially fatal disease that typically occurs in the third trimester, (45) but may present as early as 22 weeks of gestation, and in up to 20% postnatally. Incidence of AFLP is increased in multigravidas, male fetus, first pregnancy, previous AFLP (recurrence rate of 20%), maternal metabolic disorders (e.g., type 2 diabetes), and fetal fatty acid oxidation disorders (FAODs) with deficiencies of specific enzymes involved in mitochondrial metabolism of fatty acids.…”

Section: Hepatitis E Virusmentioning

confidence: 99%

Liver Diseases in the Perinatal Period: Interactions Between Mother and Infant

et al. 2020

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Liver diseases affecting the mother and infant dyad may present in the perinatal period from 20 weeks of gestation to 28 days of life. This review will focus on the current approach to neonatal acute liver failure and the progress made in the diagnosis and management of gestational alloimmune liver disease. It will highlight mother‐to‐child transmission of viral hepatitis, both management and public health implications. Emerging concepts implicating maternal obesity and nutrition in the development of a rapidly progressive nonalcoholic steatohepatitis phenotype in the offspring will be discussed. Finally, the presentation and management of acute fatty liver of pregnancy and intrahepatic cholestasis of pregnancy, and their impact on the fetus, will be reviewed.

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“…If we take the term 'natural substrate' to mean a substance to which an organism has been exposed and for which a transporter has a particularly high k cat or k cat /K m , it is reasonable to refer to such a molecule as a 'natural substrate', as in the ergothioneine/SLC22A4 example above. Another exogenous molecule that seems similarly valuable to mammals [93][94][95][96][97][98][99][100][101][102][103][104] and other organisms [105], albeit its uptake transporter is not yet known, is pyrroloquinoline quinone (PQQ) [106], also known as methoxatin, a redox cofactor normally associated with prokaryotes [107; 108].…”

Section: Some Mammalian Transporters With Known Selectivity For Exogementioning

confidence: 99%

Consensus rank orderings of molecular fingerprints illustrate the ‘most genuine’ similarities between marketed drugs and small endogenous human metabolites, but highlight exogenous natural products as the most important ‘natural’ drug transporter substrates

O’Hagan

Kell

2017

Preprint

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We compare several molecular fingerprint encodings for marketed, small molecule drugs, and assess how their rank order varies with the fingerprint in terms of the Tanimoto similarity to the most similar endogenous human metabolite as taken from Recon2. For the great majority of drugs, the rank order varies very greatly depending on the encoding used, and also somewhat when the Tanimoto similarity (TS) is replaced by the Tversky similarity. However, for a subset of such drugs, amounting to some 10% of the set and a Tanimoto similarity of ~0.8 or greater, the similarity coefficient is relatively robust to the encoding used. This leads to a metric that, while arbitrary, suggests that a Tanimoto similarity of 0.75-0.8 or greater genuinely does imply a considerable structural similarity of two molecules in the drug-endogenite space. Although comparatively few (<10% of) marketed drugs are, in this sense, robustly similar to an endogenite, there is often at least one encoding with which they are genuinely similar (e.g. TS > 0.75). This is referred to as the Take Your Pick Improved Cheminformatic Analytical Likeness or TYPICAL encoding, and on this basis some 66% of drugs are within a TS of 0.75 to an endogenite.We next explicitly recognise that natural evolution will have selected for the ability to transport dietary substances, including plant, animal and microbial 'secondary' metabolites, that are of benefit to the host. These should also be explored in terms of their closeness to marketed drugs. We thus compared the TS of marketed drugs with the contents of various databases of natural products. When this is done, we find that some 80% of marketed drugs are within a TS of 0.7 to a natural product, even using just the MACCS encoding. For patterned and TYPICAL encodings, 80% and 98% of drugs are within a TS of 0.8 to (an endogenite or) an exogenous natural product. This implies strongly that it is these exogeneous (dietary and medicinal) natural products that are more to be seen as the 'natural' substrates of drug transporters (as is recognised, for instance, for the solute carrier SLC22A4 and ergothioneine). This novel analysis casts an entirely different light on the kinds of natural molecules that are to be seen as most like marketed drugs, and hence potential transporter substrates, and further suggests that a renewed exploitation of natural products as drug scaffolds would be amply rewarded.

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Early PQQ supplementation has persistent long‐term protective effects on developmental programming of hepatic lipotoxicity and inflammation in obese mice

Cited by 48 publications

References 72 publications

Pyrroloquinoline quinone prevents developmental programming of microbial dysbiosis and macrophage polarization to attenuate liver fibrosis in offspring of obese mice

Pyrroloquinoline quinone prevents developmental programming of microbial dysbiosis and macrophage polarization to attenuate liver fibrosis in offspring of obese mice

Liver Diseases in the Perinatal Period: Interactions Between Mother and Infant

Consensus rank orderings of molecular fingerprints illustrate the ‘most genuine’ similarities between marketed drugs and small endogenous human metabolites, but highlight exogenous natural products as the most important ‘natural’ drug transporter substrates

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