Analysis of Molecular Mechanisms of 5-Fluorouracil Induced Steatosis and Inflammation in Vitro and in Mice

Sommer, Judith; Mahli, A; Freese, K; Thasler, Wolfgang E.; Kuecuekoktay, Fulya Suzan; Bosserhoff, A; Müller, Mira; Hellerbrand, Claus

doi:10.1016/s0168-8278(16)00226-9

Cited by 1 publication

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References 53 publications

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“…Furthermore, studies in human primary liver cells have shown that 5-fu induces mitochondrial dysfunction as a mechanism for the increased lipid accumulation, as we also see here and has been reported in experimental mouse NAFLD models 6 . c-Jun N-terminal kinase (JNK), IL-8 and fibrosis markers are also activated by 5-fu 55 similar to what is known in senescent cells. These clinical studies together with the current and other results support the contention that cell senescence is a primary driver of NAFLD/NASH.…”

Section: Discussionmentioning

confidence: 62%

BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD/NASH

et al. 2022

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The role of hepatic cell senescence in human non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is not well understood. To examine this, we performed liver biopsies and extensive characterization of 58 individuals with or without NAFLD/NASH. Here, we show that hepatic cell senescence is strongly related to NAFLD/NASH severity, and machine learning analysis identified senescence markers, the BMP4 inhibitor Gremlin 1 in liver and visceral fat, and the amount of visceral adipose tissue as strong predictors. Studies in liver cell spheroids made from human stellate and hepatocyte cells show BMP4 to be anti-senescent, anti-steatotic, anti-inflammatory and anti-fibrotic, whereas Gremlin 1, which is particularly highly expressed in visceral fat in humans, is pro-senescent and antagonistic to BMP4. Both senescence and anti-senescence factors target the YAP/TAZ pathway, making this a likely regulator of senescence and its effects. We conclude that senescence is an important driver of human NAFLD/NASH and that BMP4 and Gremlin 1 are novel therapeutic targets.

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Section: Discussionmentioning

confidence: 62%