A role of peroxisome proliferator‐activated receptor γ in non‐alcoholic fatty liver disease

Skat-Rørdam, Josephine; Ipsen, David Højland; Lykkesfeldt, Jens; Tveden‐Nyborg, Pernille

doi:10.1111/bcpt.13190

Cited by 137 publications

(101 citation statements)

References 75 publications

(133 reference statements)

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“…The multi-layer and multi-angle function of PPARγ have been confirmed by many researchers. 95,96 As we mentioned above, PPARγ activation down-regulate inflammatory response, 97 inhibit HSCs activation, 98 increase energy expenditure 99 and increase insulin sensitivity. 100 PPARγ activation could stimulate fatty acid oxidation in the liver.…”

Section: Pparγ Natural Agonists In Non-alcoholic Fatty Liver Diseasmentioning

confidence: 96%

Therapeutic potential of PPARγ natural agonists in liver diseases

Guo

2020

J Cellular Molecular Medi

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Peroxisome proliferator‐activated receptor gamma (PPARγ) is a vital subtype of the PPAR family. The biological functions are complex and diverse. PPARγ plays a significant role in protecting the liver from inflammation, oxidation, fibrosis, fatty liver and tumours. Natural products are a promising pool for drug discovery, and enormous research effort has been invested in exploring the PPARγ‐activating potential of natural products. In this manuscript, we will review the research progress of PPARγ agonists from natural products in recent years and probe into the application potential and prospects of PPARγ natural agonists in the therapy of various liver diseases, including inflammation, hepatic fibrosis, non‐alcoholic fatty liver and liver cancer.

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Section: Pparγ Natural Agonists In Non-alcoholic Fatty Liver Diseasmentioning

confidence: 96%

Therapeutic potential of PPARγ natural agonists in liver diseases

Guo

2020

J Cellular Molecular Medi

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“…Hepatic expression levels of PPARg are significantly increased in patients with NAFLD. 35 The role of CCR2 in liver cancer has been studied before. The CCR2 antagonist RDC018 (GSK) was shown to suppress liver tumor growth and postsurgical recurrence in subcutaneous liver tumor models.…”

Section: Cd4 -mentioning

confidence: 99%

Roles of CCR2 and CCR5 for Hepatic Macrophage Polarization in Mice With Liver Parenchymal Cell-Specific NEMO Deletion

Bartneck

Koppe

Fech

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Macrophages critically regulate liver inflammation. Using a genetically determined hepatitis mouse model we found that CCR2 controls monocyte and macrophage recruitment to injured livers, while CCR5-dependent functions of liver macrophages limit hepatic injury, thereby reducing steatosis and hepatocarcinogenesis. BACKGROUND & AIMS: Macrophages are key regulators of inflammation and cancer promotion in the liver, and their recruitment and activation is linked to chemokine receptor signaling. However, the exact roles of the chemokine receptors CCR2 and CCR5 for macrophage functions in the liver is obscure. METHODS: To study CCR2 and CCR5 in inflammatory liver injury, we used mice with a hepatocyte-specific knockout of the nuclear factor kB (NF-kB) essential modulator (NEMO), termed NEMO LPC-KO mice, and generated NEMO LPC-KO Ccr2-/and NEMO LPC-KO Ccr5-/mice. NEMO LPC-KO mice develop hepatitis and fibrosis after two and liver tumors after six months. RESULTS: We found that both CCR2 and CCR5 deficiency led to reduced fibrosis, while CCR5 deficiency increased steatosis and tumor burden in NEMO LPC-KO mice. CCR2 was required for recruitment of hepatic macrophages, whereas CCR5 promoted stellate cell activation. The reduction of monocytes and macrophages by either anti-Gr1 antibody or clodronate-loaded liposomes (CLL), but not of CD8 þ T cells or NK cells, significantly aggravated liver injury in NEMO LPC-KO mice and was further increased in NEMO LPC-KO Ccr5-/mice. CLLinduced liver injury was dampened by the adoptive transfer of ex vivo generated macrophages, whereas the adoptive transfer of control CD115 þ immature monocytes or B cells did not reduce liver injury. CONCLUSIONS: Although CCR2 and CCR5 principally promote liver fibrosis, they exert differential functions on hepatic macrophages during liver disease progression in NEMO LPC-KO mice. While CCR2 controls the recruitment of monocytes to injured livers, CCR5-dependent functions of liver macrophages limit hepatic injury, thereby reducing steatosis and hepatocarcinogenesis.

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“…Hepatic peroxisome proliferator-activated receptor gamma (PPARγ, Pparg) and the PPARγ-regulated fatty acid translocase (FAT/CD36, Cd36) expression is increased in mice fed the MCD diets [5-7, 11, 12]. Both PPARγ [13][14][15] and CD36 [16] contribute to the development of high-fat diet-induced steatosis in mice by upregulating steatogenic mechanisms that involve de novo lipogenesis (DNL) and fatty acid uptake [15,17]. In addition, hepatic PPARγ and CD36 expression is positively associated with the progression of NAFLD in mice and humans [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Loss of Hepatocyte-Specific PPARγ Expression Ameliorates Early Events of Steatohepatitis in Mice Fed the Methionine and Choline-Deficient Diet

Córdoba-Chacón

2020

PPAR Research

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The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. To date, there is not a specific and approved treatment for NAFLD yet, and therefore, it is important to understand the molecular mechanisms that lead to the progression of NAFLD. Methionine- and choline-deficient (MCD) diets are used to reproduce some features of NAFLD in mice. MCD diets increase the expression of hepatic peroxisome proliferator-activated receptor gamma (PPARγ, Pparg) and the fatty acid translocase (CD36, Cd36) which could increase hepatic fatty acid uptake and promote the progression of NAFLD in mice and humans. In this study, we assessed the contribution of hepatocyte-specific PPARγ and CD36 expression to the development of early events induced by the MCD diet. Specifically, mice with adult-onset, hepatocyte-specific PPARγ knockout with and without hepatocyte CD36 overexpression were fed a MCD diet for three weeks. Hepatocyte PPARγ and/or CD36 expression did not contribute to the development of steatosis induced by the MCD diet. However, the expression of inflammatory and fibrogenic genes seems to be dependent on the expression of hepatocyte PPARγ and CD36. The expression of PPARγ and CD36 in hepatocytes may be relevant in the regulation of some features of NAFLD and steatohepatitis.

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A role of peroxisome proliferator‐activated receptor γ in non‐alcoholic fatty liver disease

Cited by 137 publications

References 75 publications

Therapeutic potential of PPARγ natural agonists in liver diseases

Therapeutic potential of PPARγ natural agonists in liver diseases

Roles of CCR2 and CCR5 for Hepatic Macrophage Polarization in Mice With Liver Parenchymal Cell-Specific NEMO Deletion

Loss of Hepatocyte-Specific PPARγ Expression Ameliorates Early Events of Steatohepatitis in Mice Fed the Methionine and Choline-Deficient Diet

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