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Perilipin5 protects against non-alcoholic steatohepatitis by increasing 11-Dodecenoic acid and inhibiting the occurrence of ferroptosis

Nutrition & Metabolism · 9 authors, 2 centres

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TL;DR

In mouse models of NASH, knockout of the Plin5 gene worsened liver inflammation, fibrosis, and ferroptosis, while overexpressing Plin5 alleviated these conditions. The protective effect was linked to increased levels of 11-Dodecenoic acid, a monounsaturated fatty acid that inhibits ferroptosis.

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This preclinical study investigated the role of Perilipin5 (Plin5) in non-alcoholic steatohepatitis (NASH) using wild-type and Plin5 knockout mice fed high-fat/high-cholesterol (HFHC) or methionine choline-deficient (MCD) diets. The study found that hepatic Plin5 expression was reduced in NASH models. Plin5 knockout exacerbated NASH features, including lipid accumulation, inflammation, fibrosis, and ferroptosis, as measured by key gene expression and lipid peroxide levels. Conversely, adenoviral overexpression of Plin5 in mouse livers alleviated ferroptosis and MCD-induced NASH progression. Targeted lipidomics revealed that the monounsaturated fatty acid 11-Dodecenoic acid was significantly decreased in Plin5 knockout mouse livers. Cell experiments suggested that adding 11-Dodecenoic acid to Plin5-knockdown hepatocytes prevented ferroptosis. Limitations include the use of systemic knockout models, which may not fully represent tissue-specific effects, and the need for further research into the precise molecular mechanisms linking Plin5, 11-Dodecenoic acid, and ferroptosis. The findings suggest Plin5 may be a therapeutic target for NASH management by modulating lipid metabolism and inhibiting ferroptosis.

STUDY TYPE

other

SPECIALTY

gastroenterology

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AI pipeline

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ORIGINAL PAPER

PMC10286369

Perilipin5 protects against non-alcoholic steatohepatitis by increasing 11-Dodecenoic acid and inhibiting the occurrence of ferroptosis

Nutrition & Metabolism

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ABSTRACT

Background Non-alcoholic steatohepatitis (NASH) is a major contributor to liver cirrhosis and hepatocellular carcinoma. There remains no effective pharmacological therapy. The hepatic lipid metabolism and fatty acid β-oxidation are regulated by Perilipin5 (Plin5). However, it is yet unknown how Plin5 affects NASH and the molecular process. Methods High-fat, high-cholesterol and high-fructose (HFHC) diets were used to mimic the progression of NASH in wild type (WT) mice and Plin5 knockout (Plin5 KO) mice. The degree of ferroptosis was measured by detecting the expression of key genes of ferroptosis and the level of lipid peroxide. The degree of NASH was judged by observing the morphology of the liver, detecting the expression of inflammation and fibrosis related genes of liver damage. Plin5 was overexpressed in the liver of mice by tail vein injection of adenovirus, and the process of NASH was simulated by methionine choline deficiency (MCD) diet. The occurrence of ferroptosis and NASH was detected by the same detection method. Targeted lipidomics sequencing was used to detect the difference in free fatty acid expression in the WT Plin5 KO group. Finally, it was verified in cell experiments to further study the effect of free fatty acids on ferroptosis of hepatocytes. Results In various NASH models, hepatic Plin5 was dramatically reduced. Plin5 knockout (KO) worsened NASH-associated characteristics in mice given a high-fat/high-cholesterol (HFHC) diet, such as lipid accumulation, inflammation and hepatic fibrosis. It has been shown that ferroptosis is involved in NASH progression. We revealed that Plin5 KO in mice aggravated the degree of ferroptosis in NASH models. Conversely, overexpression of Plin5 significantly alleviated ferroptosis and further ameliorated progression of MCD-induced NASH. Analysis of livers obtained from HFHC diet-fed mice by targeted lipidomics revealed that 11-Dodecenoic acid was significantly decreased in Plin5 KO mice. Addition of 11-Dodecenoia acid to Plin5 knockdown hepatocytes effectively prevented ferroptosis. Conclusion Our study demonstrates that Plin5 protects against NASH progression by increasing 11-Dodecenoic acid level and further inhibiting ferroptosis, suggesting that Plin5 has therapeutic potential as a target for the management of NASH. Supplementary Information The online version contains supplementary material available at 10.1186/s12986-023-00751-2.

CITATION EXPORT

Xinming Xu, Jin Qiu, Xiaoya Li et al.. Perilipin5 protects against non-alcoholic steatohepatitis by increasing 11-Dodecenoic acid and inhibiting the occurrence of ferroptosis. Nutrition & Metabolism. (2023). https://doi.org/10.1186/s12986-023-00751-2

AUTHORS

9 · 2 CENTRES

Xinming Xu, Jin Qiu, Xiaoya Li, Juntong Chen, Yue Li, Xinmei Huang, Shufei Zang, Xinran Ma, Jun Liu

1grid.8547.e0000 0001 0125 2443Department of Endocrinology, Shanghai Fifth People’s Hospital, Fudan University, 801 Heqing Road, Shanghai, 200240 China
2grid.22069.3f0000 0004 0369 6365Shanghai Key Laboratory of Regulatory Biological, Institute of Biomedical Science, School of Life Science, East China Normal University, Shanghai, 200241 China