Hepatocyte mARC1 promotes fatty liver disease

Lewis, Lara C.; Chen, Lingyan; Hameed, L.Shahul; Kitchen, Robert; Maroteau, Cyrielle; Nagarajan, Shilpa R.; Norlin, Jenny; Daly, Charlotte E.; Szczerbinska, Iwona; Hjuler, Sara Toftegaard; Patel, Rahul; Livingstone, Eilidh; Durrant, Tom N.; Wondimu, Elisabeth; BasuRay, Soumik; Chandran, Anandhakumar; Lee, Wan-Hung; Hu, Sile; Gilboa, Barak; Grandi, Megan E.; Toledo, Enrique M.; Erikat, Abdullah H.A.; Hodson, Leanne; Haynes, William G.; Pursel, Natalie W.; Coppieters, Ken; Fleckner, Jan; Howson, Joanna M.M.; Andersen, Birgitte; Ruby, Maxwell A.

doi:10.1016/j.jhepr.2023.100693

Cited by 18 publications

(19 citation statements)

References 33 publications

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“…A recent study on primary human hepatocytes and mouse knockdown model confirmed the protection effect of Marc1 deficiency on diet‐induced steatosis and fibrosis. Interestingly, this study suggested that the physiological effect of Marc1 knockdown may act through Kennedy pathway, a phospholipid de novo synthesis pathway, and fatty acid metabolism 24 . These results consistently implied the potential roles of phospholipids in NAFLD pathogenesis and connected it to mitochondria function.…”

Section: Marc1supporting

confidence: 65%

Unraveling the pathogenesis of non‐alcoholic fatty liver diseases through genome‐wide association studies

Tian,

Wang

2023

J of Gastro and Hepatol

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Non‐alcoholic fatty liver disease (NAFLD) is a significant health burden around the world, affecting approximately 25% of the population. Recent advances in human genetic databases have allowed for the identification of various single nucleotide polymorphisms associated with NAFLD‐related traits. Investigating the functions of these genetic factors provides insight into the pathogenesis of NAFLD and potentially identifies novel therapeutic targets for NAFLD. In this review, we summarized current research on genes with NAFLD‐associated mutations, highlighting phospholipid remodeling and spatially clustered loci as common pathological and genetic features of these mutations. These features suggest a complex yet intriguing mechanism of dissociated steatosis and insulin resistance, which is observed in a subset of patients and may lead to more precise therapy against NAFLD in the future.

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Section: Marc1supporting

confidence: 65%

Unraveling the pathogenesis of non‐alcoholic fatty liver diseases through genome‐wide association studies

Tian,

Wang

2023

J of Gastro and Hepatol

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“…Notwithstanding, the connection between mARC1 and liver disease has been confirmed by numerous other GWAS [100,[103][104][105][106][107][108]. NAFLD is a very prevalent disease; the number of patients affected by NAFLD in the United States alone is expected to exceed 100 million by 2030, with 27% of these cases progressing to NASH.…”

Section: Marc Enzymes In Human Diseasementioning

confidence: 87%

“…There are, as of yet, no pharmacotherapeutic options for the treatment and prevention of NAFLD and NASH [109]. mARC1 might represent an interesting drug target, especially in obese patients with a high risk of liver mortality [103,108]. Consequently, many pharmaceutical companies are currently investigating si-RNA-based approaches for targeted reduction of mARC1 expression levels in the liver (see Table 1).…”

Section: Marc Enzymes In Human Diseasementioning

confidence: 99%

The History of mARC

Clement

Struwe

2023

Molecules

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The mitochondrial amidoxime-reducing component (mARC) is the most recently discovered molybdoenzyme in humans after sulfite oxidase, xanthine oxidase and aldehyde oxidase. Here, the timeline of mARC’s discovery is briefly described. The story begins with investigations into N-oxidation of pharmaceutical drugs and model compounds. Many compounds are N-oxidized extensively in vitro, but it turned out that a previously unknown enzyme catalyzes the retroreduction of the N-oxygenated products in vivo. After many years, the molybdoenzyme mARC could finally be isolated and identified in 2006. mARC is an important drug-metabolizing enzyme and N-reduction by mARC has been exploited very successfully for prodrug strategies, that allow oral administration of otherwise poorly bioavailable therapeutic drugs. Recently, it was demonstrated that mARC is a key factor in lipid metabolism and likely involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). The exact link between mARC and lipid metabolism is not yet fully understood. Regardless, many now consider mARC a potential drug target for the prevention or treatment of liver diseases. This article focusses on discoveries related to mammalian mARC enzymes. mARC homologues have been studied in algae, plants and bacteria. These will not be discussed extensively here.

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“…However, inhibitors of mARC may be useful in the treatment of NAFLD. 24 In this context, the development of a simple highthroughput screening protocol is necessary to identify previously unknown inhibitors, particularly of mARC-1, as shown by the influence of DMSO in Supporting Information Figure S13.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The mARC enzyme system not only plays a role in drug metabolism but may also have an impact on diseases: in the last years, genome-wide association studies have demonstrated that mutations in the MTARC1 gene are related to protective effects against nonalcoholic fatty liver disease (NAFLD). − Despite the fact that various endogenous and exogenous substances are reduced by mARC, the physiological role of mARC with respect to NAFLD still remains unclear. However, inhibitors of mARC may be useful in the treatment of NAFLD . In this context, the development of a simple high-throughput screening protocol is necessary to identify previously unknown inhibitors, particularly of mARC-1, as shown by the influence of DMSO in Supporting Information Figure S13.…”

Section: Introductionmentioning

confidence: 99%

New Design of an Activity Assay Suitable for High-Throughput Screening of Substrates and Inhibitors of the Mitochondrial Amidoxime Reducing Component (mARC)

Klopp,

Struwe,

Plieth

et al. 2023

Anal. Chem.

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The mitochondrial amidoxime-reducing component (mARC) is one of the simplest molybdenum-containing enzymes. mARC is among a few known reducing enzymes playing an important role in drug metabolism in mammals. Here, an assay based on the fluorescence of NADH is reported for the rapid detection of substrates and potential inhibitors of mARC. So far unknown inhibitors might be useful for the development of drugs assigned to nonalcoholic fatty liver disease (NAFLD) and similar diseases. Kinetics of reactions catalyzed by mARC can be recorded with high sensitivity and precision. On a microtiter plate scale, the assay presented could be applied for highthroughput screening of substance libraries and detection of novel mARC substrate candidates. For instance, molnupiravir was also identified as a new substrate by this assay. For better comparison for such substances, the inhibitor or substrate-to-BAO ratio was introduced. After normalization of enzyme activities to the standard benzamidoxime, substrates can reproducibly be classified.

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Hepatocyte mARC1 promotes fatty liver disease

Cited by 18 publications

References 33 publications

Unraveling the pathogenesis of non‐alcoholic fatty liver diseases through genome‐wide association studies

Unraveling the pathogenesis of non‐alcoholic fatty liver diseases through genome‐wide association studies

The History of mARC

New Design of an Activity Assay Suitable for High-Throughput Screening of Substrates and Inhibitors of the Mitochondrial Amidoxime Reducing Component (mARC)

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