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

Lee, Samuel M; Muratalla, Jose; Karimi, Saman; Díaz‐Ruiz, Alberto; Frutos, María Dolores; Guzman, Grace; Ramos‐Molina, Bruno; Córdoba-Chacón, José

doi:10.1007/s00018-022-04629-z

Cited by 19 publications

(15 citation statements)

References 67 publications

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“…It is well known that mice fed a high-fat diet show increased expression of hepatic PPARγ (Inoue et al 2005), and the activator protein 1 (AP-1, Fos/Jun) complex activate the expression of PPARγ2 in hepatocytes of mice fed a high-fat diet (Hasenfuss et al 2014). This would be in line with early studies by Vidal-Puig et al that showed a dietary (highfat diet)-mediated upregulation of PPARγ2 in adipose tissue (Vidal-Puig et al 1996, 1997, as well as our recent study that shows how high-fat diet increases PPARγ2 levels in male and female mice (Lee et al 2023). Thereby, although PPARγ is expressed at low levels in the livers of lean patients (Vidal-Puig et al 1997), its expression (or the pathways controlled by PPARγ in the liver) is significantly increased in patients with NAFLD/NASH (Nakamuta et al 2005, Lima-Cabello et al 2011, Pettinelli & Videla 2011, Jia & Zhai 2019, Namjou et al 2019, Frohlich et al 2020, Lee et al 2023.…”

Section: Cell-specific Expression Of Pparγ and Potential Cell-specifi...supporting

confidence: 92%

“…This would be in line with early studies by Vidal-Puig et al that showed a dietary (highfat diet)-mediated upregulation of PPARγ2 in adipose tissue (Vidal-Puig et al 1996, 1997, as well as our recent study that shows how high-fat diet increases PPARγ2 levels in male and female mice (Lee et al 2023). Thereby, although PPARγ is expressed at low levels in the livers of lean patients (Vidal-Puig et al 1997), its expression (or the pathways controlled by PPARγ in the liver) is significantly increased in patients with NAFLD/NASH (Nakamuta et al 2005, Lima-Cabello et al 2011, Pettinelli & Videla 2011, Jia & Zhai 2019, Namjou et al 2019, Frohlich et al 2020, Lee et al 2023. Specifically, we have measured the expression of PPARγ in a cohort of 102 patients with severe obesity and found that obese patients with NAFLD/NASH (70% of the cohort) have increased the expression of PPARγ and PPARγ-target genes in the liver (Lee et al 2023).…”

Section: Cell-specific Expression Of Pparγ and Potential Cell-specifi...supporting

confidence: 92%

“…Thereby, although PPARγ is expressed at low levels in the livers of lean patients (Vidal-Puig et al 1997), its expression (or the pathways controlled by PPARγ in the liver) is significantly increased in patients with NAFLD/NASH (Nakamuta et al 2005, Lima-Cabello et al 2011, Pettinelli & Videla 2011, Jia & Zhai 2019, Namjou et al 2019, Frohlich et al 2020, Lee et al 2023. Specifically, we have measured the expression of PPARγ in a cohort of 102 patients with severe obesity and found that obese patients with NAFLD/NASH (70% of the cohort) have increased the expression of PPARγ and PPARγ-target genes in the liver (Lee et al 2023). Similarly, the expression of PPARγ is also increased in the livers of mouse models with NAFLD, suggesting that PPARγ is a steatogenic factor that contributes to the progression of this disease (Gavrilova et al 2003, Inoue et al 2005, Morán-Salvador et al 2011, Gao et al 2016, Wolf Greenstein et al 2017, de Conti et al 2020, Lee et al 2021a.…”

Section: Cell-specific Expression Of Pparγ and Potential Cell-specifi...mentioning

confidence: 99%

“…To test the contribution of PPARγ in hepatocytes, PPARγ has been mostly knocked out using the Alb promoterdriven Cre recombinase: Pparg ΔHep (Gavrilova et al 2003, Morán-Salvador et al 2011, Moran-Salvador et al 2013, Zhang et al 2016, Kulkarni et al 2020. Our research group has used adenoassociated virus serotype 8 to deliver a thyroxin-binding globulin (TBG) promoter-driven Cre recombinase (AAV8-TBG-Cre) to generate Pparg ΔHep in adult mice (Wolf Greenstein et al 2017, Cordoba-Chacon 2020, Lee et al 2021a,b, Lee et al 2023) (Table 2). The generation of Pparg ΔHep mice clearly shows that PPARγ serves as a steatogenic factor in hepatocytes.…”

Section: Contribution Of Hepatocyte-specific Pparγ To the Phenotype O...mentioning

confidence: 99%

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Role of hepatic peroxisome proliferator-activated receptor γ in non-alcoholic fatty liver disease

Lee

Muratalla

Sierra‐Cruz

et al. 2023

Journal of Endocrinology

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Peroxisome proliferator-activated receptor γ (PPARγ) belongs to a family of nuclear receptors that could serve as lipid sensors. PPARγ is the target of a group of insulin sensitizers called thiazolidinediones (TZD) which regulate the expression of genes involved in glucose and lipid metabolism, as well as adipokines that regulate metabolic function in other tissues. Non-alcoholic fatty liver disease (NAFLD) has a high prevalence worldwide and is even higher in patients with obesity and insulin resistance. TZD-mediated activation of PPARγ could serve as a good treatment for NAFLD because TZD have shown anti-fibrogenic and anti-inflammatory effects in vitro, and increase insulin sensitivity in peripheral tissues which improves liver pathology. However, mechanistic studies in mouse models suggest that the activation of PPARγ in hepatocytes might reduce or limit the therapeutic potential of TZD against NAFLD. In this review, we briefly describe the short history of PPAR isoforms, the relevance of their expression in different tissues, as well as the pathogenesis and potential therapeutics for NAFLD. We also discuss some evidence derived from mouse models that could be useful for endocrinologists to assess tissue-specific roles of PPARs, complement reverse endocrinology approaches, and understand the direct role that PPARγ has in hepatocytes and non-parenchymal cells.

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Section: Cell-specific Expression Of Pparγ and Potential Cell-specifi...supporting

confidence: 92%

Section: Cell-specific Expression Of Pparγ and Potential Cell-specifi...supporting

confidence: 92%

Section: Cell-specific Expression Of Pparγ and Potential Cell-specifi...mentioning

confidence: 99%

Section: Contribution Of Hepatocyte-specific Pparγ To the Phenotype O...mentioning

confidence: 99%

See 2 more Smart Citations

Role of hepatic peroxisome proliferator-activated receptor γ in non-alcoholic fatty liver disease

Lee

Muratalla

Sierra‐Cruz

et al. 2023

Journal of Endocrinology

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“…Mouse liver expression of Pparg (PPAR-γ), like that for the Me1 gene, is increased by high-fat diets and mainly occurs within the hepatocyte [ 14 , 51 ]. Since liver-expressed Pparg and Me1 genes are both associated with hepatosteatosis [ 6 , 26 , 51 , 52 , 53 ], the reduced steatosis observed in our female obese MOD-1 mice is likely due, in part, to reduced Pparg and absent ME1 expression. The physiological linkages of ME1 and PPAR-γ raise the question of the relevant molecular connection(s).…”

Section: Discussionmentioning

confidence: 99%

Malic Enzyme 1 (ME1) Promotes Adiposity and Hepatic Steatosis and Induces Circulating Insulin and Leptin in Obese Female Mice

Simmen

Pabona

Al‐Dwairi

et al. 2023

IJMS

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Malic Enzyme 1 (ME1) supports lipogenesis, cholesterol synthesis, and cellular redox potential by catalyzing the decarboxylation of L-malate to pyruvate, and the concomitant reduction of NADP to NADPH. We examined the contribution of ME1 to the development of obesity by provision of an obesogenic diet to C57BL/6 wild type (WT) and MOD-1 (lack ME1 protein) female mice. Adiposity, serum hormone levels, and adipose, mammary gland, liver, and small intestine gene expression patterns were compared between experimental groups after 10 weeks on a diet. Relative to WT female mice, MOD-1 female mice exhibited lower body weights and less adiposity; decreased concentrations of insulin, leptin, and estrogen; higher concentrations of adiponectin and progesterone; smaller-sized mammary gland adipocytes; and reduced hepatosteatosis. MOD-1 mice had diminished expression of Lep gene in abdominal fat; Lep, Pparg, Klf9, and Acaca genes in mammary glands; Pparg and Cdkn1a genes in liver; and Tlr9 and Ffar3 genes in the small intestine. By contrast, liver expression of Cdkn2a and Lepr genes was augmented in MOD-1, relative to WT mice. Results document an integrative role for ME1 in development of female obesity, suggest novel linkages with specific pathways/genes, and further support the therapeutic targeting of ME1 for obesity, diabetes, and fatty liver disease.

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Lipid sensing nuclear receptors involved in the pathogenesis of fatty liver disease

Schweiger,

Arredondo‐Lasso,

Friano

et al. 2024

FEBS Letters

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

Cited by 19 publications

References 67 publications

Role of hepatic peroxisome proliferator-activated receptor γ in non-alcoholic fatty liver disease

Role of hepatic peroxisome proliferator-activated receptor γ in non-alcoholic fatty liver disease

Malic Enzyme 1 (ME1) Promotes Adiposity and Hepatic Steatosis and Induces Circulating Insulin and Leptin in Obese Female Mice

Lipid sensing nuclear receptors involved in the pathogenesis of fatty liver disease

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