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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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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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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DOI: https://doi.org/10.1007/s00018-022-04629-z