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- Salomone, Federico, et al.
(författare)
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SIRT5 rs12216101 T>G variant is associated with liver damage and mitochondrial dysfunction in patients with non-alcoholic fatty liver disease
- 2024
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Ingår i: JOURNAL OF HEPATOLOGY. - 0168-8278 .- 1600-0641. ; 80:1, s. 10-19
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Sirtuin 5, encoded by the SIRT5 gene, is a NAD+ -dependent deacylase that modulates mitochondrial metabolic processes through post-translational modifications. In this study, we aimed to examine the impact of the SIRT5 rs12216101 T>G non-coding single nucleotide polymorphism on disease severity in patients with non-alcoholic fatty liver disease (NAFLD). Methods: The rs12216101 variant was genotyped in 2,606 consecutive European patients with biopsy-proven NAFLD. Transcriptomic analysis, expression of mitochondrial complexes and oxidative stress levels were measured in liver samples from a subset of bariatric patients. Effects of SIRT5 pharmacological inhibition were evaluated in HepG2 cells exposed to excess free fatty acids. Mitochondrial energetics in vitro were investigated by high-performance liquid chromatography. Results: In the whole cohort, the frequency distribution of SIRT5 rs12216101 TT, TG and GG genotypes was 47.0%, 42.3% and 10.7%, respectively. At multivariate logistic regression analysis adjusted for sex, age >50 years, diabetes, and PNPLA3 rs738409 status, the SIRT5 rs12216101 T>G variant was associated with the presence of non-alcoholic steatohepatitis (odds ratio 1.20, 95% CI 1.03-1.40) and F2-F4 fibrosis (odds ratio 1.18; 95% CI 1.00-1.37). Transcriptomic analysis showed that the SIRT5 rs12216101 T>G variant was associated with upregulation of transcripts involved in mitochondrial metabolic pathways, including the oxidative phosphorylation system. In patients carrying the G allele, western blot analysis confirmed an upregulation of oxidative phosphorylation complexes III, IV, V and consistently higher levels of reactive oxygen species, reactive nitrogen species and malondialdehyde, and lower ATP levels. Administration of a pharmacological SIRT5 inhibitor preserved mitochondrial energetic homeostasis in HepG2 cells, as evidenced by restored ATP/ADP, NAD+/NADH, NADP+/NADPH ratios and glutathione levels. Conclusions: The SIRT5 rs12216101 T>G variant, heightening SIRT5 activity, is associated with liver damage, mitochondrial dysfunction, and oxidative stress in patients with NAFLD. (c) 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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| 2. |
- Sasidharan, Kavitha, et al.
(författare)
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IL32 downregulation lowers triglycerides and type I collagen in di-lineage human primary liver organoids.
- 2024
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Ingår i: Cell reports. Medicine. - 2666-3791. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Steatotic liver disease (SLD) prevails as the most common chronic liver disease yet lack approved treatments due to incomplete understanding of pathogenesis. Recently, elevated hepatic and circulating interleukin 32 (IL-32) levels were found in individuals with severe SLD. However, the mechanistic link between IL-32 and intracellular triglyceride metabolism remains to be elucidated. We demonstrate invitro that incubation with IL-32β protein leads to an increase in intracellular triglyceride synthesis, while downregulation of IL32 by small interfering RNA leads to lower triglyceride synthesis and secretion in organoids from human primary hepatocytes. This reduction requires the upregulation of Phospholipase A2 group IIA (PLA2G2A). Furthermore, downregulation of IL32 results in lower intracellular type I collagen levels in di-lineage human primary hepatic organoids. Finally, we identify a genetic variant of IL32 (rs76580947) associated with lower circulating IL-32 and protection against SLD measured by non-invasive tests. These data suggest that IL32 downregulation may be beneficial against SLD.
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