High-fat diet induces fibrosis in mice lacking CYP2A5 and PPARα: a new model for steatohepatitis-associated fibrosis

Chen, Xue; Acquaah‐Mensah, George; Denning, Krista L.; Peterson, Jonathan M.; Wang, Kesheng; Denvir, James; Hong, Feng; Cederbaum, Arthur I.; Lu, Yongke

doi:10.1152/ajpgi.00213.2020

Cited by 9 publications

(5 citation statements)

References 45 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Synthetic PPARα agonists such as fibrates lower triglyceride levels and raise high density lipoprotein (HDL), and are used to treat severe hypertriglyceridemia ( 73 ). PPARα knockout mice display a fatty liver phenotype ( 74 , 75 ). Overexpression of PPARα improves glucose tolerance in diet-induced obese mice ( 76 ).…”

Section: Peroxisome Proliferator-activated Receptors (Ppars) Regulationmentioning

confidence: 99%

The Structure Basis of Phytochemicals as Metabolic Signals for Combating Obesity

Xiao-ping

Zheng²,

Zhang³

et al. 2022

Front. Nutr.

View full text Add to dashboard Cite

The consumption of phytochemicals, bioactive compounds in fruits and vegetables, has been demonstrated to ameliorate obesity and related metabolic symptoms by regulating specific metabolic pathways. This review summarizes the progress made in our understanding of the potential of phytochemicals as metabolic signals: we discuss herein selected molecular mechanisms which are involved in the occurrence of obesity that may be regulated by phytochemicals. The focus of our review highlights the regulation of transcription factors toll like receptor 4 (TLR4), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), the peroxisome proliferator-activated receptors (PPARs), fat mass and obesity-associated protein (FTO) and regulation of microRNAs (miRNA). In this review, the effect of phytochemicals on signaling pathways involved in obesity were discussed on the basis of their chemical structure, suggesting molecular mechanisms for how phytochemicals may impact these signaling pathways. For example, compounds with an isothiocyanate group or an α, β-unsaturated carbonyl group may interact with the TLR4 signaling pathway. Regarding Nrf2, we examine compounds possessing an α, β-unsaturated carbonyl group which binds covalently with the cysteine thiols of Keap1. Additionally, phytochemical activation of PPARs, FTO and miRNAs were summarized. This information may be of value to better understand how specific phytochemicals interact with specific signaling pathways and help guide the development of new drugs to combat obesity and related metabolic diseases.

show abstract

Section: Peroxisome Proliferator-activated Receptors (Ppars) Regulationmentioning

confidence: 99%

The Structure Basis of Phytochemicals as Metabolic Signals for Combating Obesity

Xiao-ping

Zheng²,

Zhang³

et al. 2022

Front. Nutr.

View full text Add to dashboard Cite

show abstract

“…For example, expression of PPARα in human liver is reduced in NAFLD patients and negatively correlates with NAFLD severity [12]. Interestingly, in the mice lacking cytochrome P450 2A5 (CYP2A5) i.e., cyp2a5 -/-mice, we observed an elevated basal level of PPARα but more severe ethanol-and HFD-induced steatosis [13][14][15], but when the pparα -/-/cyp2a5 -/-mice are created to abrogate the upregulated PPARα, HFD-induced steatosis was more pronounced, and evident liver necroinflammation and fibrosis were observed in the pparα -/-/cyp2a5 -/-mice but not in the cyp2a5 -/-mice or pparα -/-mice [14,15], suggesting that PPARα is still protective against the HFDinduced steatosis, steatohepatitis, and fibrosis.…”

Section: Introductionmentioning

confidence: 79%

Hepatocyte-Specific PEX16 Abrogation in Mice Leads to Hepatocyte Proliferation, Alteration of Hepatic Lipid Metabolism, and Resistance to High Fat Diet (HFD)-Induced Hepatic Steatosis and Obesity

Chen,

Wang,

Denning

et al. 2024

Preprint

View full text Add to dashboard Cite

Obesity results in hepatic fat accumulation, i.e., steatosis. Besides the fat overload, impaired fatty acid β-oxidation also promotes steatosis. Fatty acid β-oxidation takes place in mitochondria and peroxisomes. Usually very long chain and branched-chain fatty acids are first oxidized in peroxisomes, and the resultant short chain fatty acids are further oxidized in mitochondria. Peroxisome biogenesis is regulated by peroxin 16 (PEX16). In liver-specific PEX16 knockout (Pex16Alb-Cre) mice, hepatocyte peroxisomes were absent, but hepatocytes proliferated, and liver mass was enlarged. These results suggest that normal liver peroxisomes restrain hepatocyte proliferation and liver sizes. After high fat diet (HFD) feeding, body weights were increased in PEX16 floxed (Pex16fl/fl) mice and adipose-specific PEX16 knockout (Pex16AdipoQ-Cre) mice but not in the Pex16Alb-Cre mice, suggesting that the development of obesity is regulated by liver PEX16 but not by adipose PEX16. However, it was previously reported that HFD-induced obesity in the Pex16AdipoQ-Cre mice was more severe than in the wild type mice, which was not observed until 27 weeks of HFD feeding. Thus, liver initiates the development of obesity, which is enhanced by abnormal adipocytes. HFD increased liver mass in the Pex16fl/fl mice but somehow reduced the already enlarged liver mass in the Pex16Alb-Cre mice. Basal levels of serum triglyceride, free fatty acids and cholesterol were decreased whereas serum bile acids were increased in the Pex16Alb-Cre mice, and HFD-induced steatosis was not observed in the Pex16Alb-Cre mice. These results suggest that normal liver peroxisomes contribute to the development of liver steatosis and obesity.

show abstract

“…This suggests that animal models offer poor representations of human diseases with respect to organ-specific gene expression profiles. However, PBSM analysis further revealed higher similarity scores for the commonly used animal models, such as mouse model with high-fat diet for NAFLD modeling [49] and mouse model with CCl4 induced liver fibrosis modeling [50] compared to other models including rat disease models.…”

Section: Discussionmentioning

confidence: 99%

Pathway-based similarity measurement to quantify transcriptomics similarity between human tissues and preclinical models

Parekh,

Sherfey,

Alaybeyoglu

et al. 2024

Preprint

View full text Add to dashboard Cite

Accurate clinical translation of preclinical research remains challenging, primarily due to species-specific differences and disease and patient heterogeneity. An important recent advancement has been the development of microphysiological systems that consist of multiple human cell types that recapitulate key characteristics of their respective human systems, allowing essential physiologic processes to be accurately assessed during drug development. However, an unmet need remains regarding a quantitative method to evaluate the similarity between diverse sample types for various contexts of use (CoU)-specific pathways. To address this gap, this study describes the development of pathway-based similarity measurement (PBSM), which leverages RNA-seq data and pathway-based information to assess the human relevance of preclinical models for specific CoU. PBSM offers a quantitative method to compare the transcriptomic similarity of preclinical models to human tissues, shown here as proof of concept for liver and cardiac tissues, enabling improved model selection and validation. Thus, PBSM can successfully support CoU selection for preclinical models, assess the impact of different gene sets on similarity calculations, and differentiate among various in vitro and in vivo models. PBSM has potential to reduce the translational gap in drug development by allowing quantitative evaluation of the similarity of preclinical models to human tissues, facilitating model selection, and improving understanding of context-specific applications. PBSM can serve as a foundation for enhancing the physiological relevance of in vitro models and supporting the development of more effective therapeutic interventions.

show abstract

High-fat diet induces fibrosis in mice lacking CYP2A5 and PPARα: a new model for steatohepatitis-associated fibrosis

Cited by 9 publications

References 45 publications

The Structure Basis of Phytochemicals as Metabolic Signals for Combating Obesity

The Structure Basis of Phytochemicals as Metabolic Signals for Combating Obesity

Hepatocyte-Specific PEX16 Abrogation in Mice Leads to Hepatocyte Proliferation, Alteration of Hepatic Lipid Metabolism, and Resistance to High Fat Diet (HFD)-Induced Hepatic Steatosis and Obesity

Pathway-based similarity measurement to quantify transcriptomics similarity between human tissues and preclinical models

Contact Info

Product

Resources

About