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Hepatocyte PPARγ contributes to the progression of non-alcoholic steatohepatitis in male and female obese mice

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Abstract

Non-alcoholic steatohepatitis (NASH) is associated with obesity and increased expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ). However, the relevance of hepatocyte PPARγ in NASH associated with obesity is still poorly understood. In this study, hepatocyte PPARγ was knocked out (PpargΔHep) in male and female mice after the development of high-fat diet-induced obesity. The diet-induced obese mice were then maintained on their original diet or switched to a high fat, cholesterol, and fructose (HFCF) diet to induce NASH. Hepatic PPARγ expression was mostly derived from hepatocytes and increased by high fat diets. PpargΔHep reduced HFCF-induced NASH progression without altering steatosis, reduced the expression of key genes involved in hepatic fibrosis in HFCF-fed male and female mice, and decreased the area of collagen-stained fibrosis in the liver of HFCF-fed male mice. Moreover, transcriptomic and metabolomic data suggested that HFCF-diet regulated hepatic amino acid metabolism in a hepatocyte PPARγ-dependent manner. PpargΔHep increased betaine-homocysteine s-methyltransferase expression and reduced homocysteine levels in HFCF-fed male mice. In addition, in a cohort of 102 obese patients undergoing bariatric surgery with liver biopsies, 16 cases were scored with NASH and were associated with increased insulin resistance and hepatic PPARγ expression. Our study shows that hepatocyte PPARγ expression is associated with NASH in mice and humans. In male mice, hepatocyte PPARγ negatively regulates methionine metabolism and contributes to the progression of fibrosis.

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Data availability

Transcript profiling: Gene Expression Omnibus (GEO) # GSE200352.

Abbreviations

NAFLD:

Non-alcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

LF/LFD:

Low fat diet

HF/HFD:

High fat diet

HFCF:

High fat, cholesterol and fructose

BMI:

Body mass index

HbA1c:

Glycated hemoglobin A1c

HOMA-IR:

Homeostatic model assessment for insulin resistance

ALT:

Alanine aminotransferase

TG:

Triglycerides

NEFA:

Non-esterified fatty acids

GTT:

Glucose tolerance test

ITT:

Insulin tolerance test

H&E:

Hematoxylin and eosin

PPARγ:

Peroxisome proliferator-activated receptor gamma

DNL:

De novo lipogenesis

Pparg ΔHep :

Adult-onset hepatocyte-specific PPARγ knockout

TZD:

Thiazolidinediones

NAS:

NAFLD Activity Score

DEG:

Differentially expressed gene

GO:

Gene ontology

SAM:

S-adenosylmethionine

Hcy:

Homocysteine

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Acknowledgements

We thank Angelie Bacon, Danielle Pins, Dr. Gregory Norris for their technical assistance. Fixed samples and H&E-stained slides were processed by the Research Histology Core at the University of Illinois at Chicago. Metabolomics services were performed by the Metabolomics Core Facility at Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Funding

This work was supported by the National Institutes of Health K01DK125525, R01DK131038, R03DK129419 [JCC], Talento Grant 2018-T1/BMD-11966 [ADR], Institute of Health Carlos III (ISCIII) PI20/00505, CP19/00098 [BRM].

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Authors and Affiliations

  1. Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave (North Entrance) Suite E625, M/C 640, Chicago, IL, USA

    Samuel M. Lee, Jose Muratalla & Jose Cordoba-Chacon

  2. Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA

    Saman Karimi & Grace Guzman

  3. IMDEA-Food, Madrid, Spain

    Alberto Diaz-Ruiz

  4. Department of General and Digestive System Surgery, Virgen de La Arrixaca University Hospital, Murcia, Spain

    Maria Dolores Frutos

  5. Obesity and Metabolism Group, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain

    Bruno Ramos-Molina

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  1. Samuel M. Lee
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Contributions

JCC conceived and designed experiments. JCC and SML wrote the manuscript. JCC, SML, JM, and ADR performed the experiment and analyzed the data. SML, SK, and GG performed a pathological analysis of the liver sections. MDF and BRM performed the experiments in patient samples and analyzed the data. SML, JM, ADR, and BRM revised and edited the manuscript.

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Correspondence to Jose Cordoba-Chacon.

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Preprint server: An early version of this study was uploaded to bioRxiv, https://doi.org/10.1101/2022.06.06.494901.

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Lee, S.M., Muratalla, J., Karimi, S. et al. Hepatocyte PPARγ contributes to the progression of non-alcoholic steatohepatitis in male and female obese mice. Cell. Mol. Life Sci. 80, 39 (2023). https://doi.org/10.1007/s00018-022-04629-z

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