PPARα-Deficient ob/ob Obese Mice Become More Obese and Manifest Severe Hepatic Steatosis Due to Decreased Fatty Acid Oxidation

Gao, Qian; Jia, Yuzhi; Yang, Gongshe; Zhang, Xiaohong; Boddu, Prajwal; Petersen, Bryon E.; Narsingam, Saiprasad; Zhu, Yi; Thimmapaya, Bayar; Kanwar, Yashpal S.; Reddy, Janardan K.

doi:10.1016/j.ajpath.2015.01.018

Cited by 76 publications

(67 citation statements)

References 58 publications

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“…To examine if this NNT mutation affects mitochondrial remodeling, we also examined mitochondrial bioenergetic activity in another control strain (C57BL/6NJ mice – NJ mice), which contain functional NNT proteins. We examined mitochondrial alterations in ob/ob mice and control mice at 21 weeks, when liver steatosis is significant, with only some early markers of steatohepatitis in ob/ob mice . Table shows that at 21 weeks, ob/ob mice have severe hepatomegaly (liver/weight ratio) due to steatosis compared with J and NJ mice, in agreement with previous results .…”

Section: Resultssupporting

confidence: 89%

Obesity and steatosis promotes mitochondrial remodeling that enhances respiratory capacity in the liver of ob/ob mice

et al. 2018

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We investigated if obesity/steatosis promotes mitochondrial remodeling in the liver of ob/ob mice (an obesity model). Liver mitochondria from ob/ob mice (21 weeks with significant steatosis) had ~ 2-fold increases in state III respiration compared with control (C57BL/6J, C57BL/6NJ) for all respiratory substrates examined (glutamate/malate, succinate, octanoate, and glycerol 3-phosphate). A corresponding 2-fold increase in the expression of respiratory complexes (I, IV, and V) and other respiratory proteins (glycerol phosphate dehydrogenase-2 and medium-chain acyl-coenzyme A dehydrogenase) occur in liver mitochondria of mature ob/ob mice. Conversely, respiration in liver mitochondria from young ob/ob mice (6 weeks) does not differ from control with any respiratory substrates examined. Overall, mitochondrial remodeling that enhances respiration increases with obesity/steatosis in the liver of ob/ob mice.

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Section: Resultssupporting

confidence: 89%

Obesity and steatosis promotes mitochondrial remodeling that enhances respiratory capacity in the liver of ob/ob mice

et al. 2018

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“…obesity develops into hepatic steatosis, primarily due to the destruction of the balance between fatty acid storage and mobilization (46,47). in the present study, H&e-stained liver sections revealed microvesicular and macrovesicular steatosis of the liver in the HFd-fed mice compared with the normal liver structure of the standard chow diet-fed mice.…”

Section: Gs Alleviates Lipid Droplet Accumulation In Vivo and Vitrosupporting

confidence: 53%

Ginsenosides reduce body weight and ameliorate hepatic steatosis in high fat diet‑induced obese mice via endoplasmic reticulum stress and p‑STAT3/STAT3 signaling

Yao

2020

Mol Med Report

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obesity has been increasing globally for over three decades. according to previous studies, dietary obesity is usually associated with endoplasmic reticulum stress (erS) and STaT3 signaling, which result in interference with the homeostatic control of energy and lipid metabolism. Ginsenosides (GS) administered to mice will modulate adiposity and food intake; however, the mechanism of food inhibition is unknown. The aim of the present study was to investigate whether GS may inhibit erS and regulate STaT3 phosphorylation in GT1-7 cells (a mouse hypothalamus gonadotropin-releasing hormone neuron cell line) and the hypothalamus in order to reduce the body weight and ameliorate hepatic steatosis in high fat diet (HFd)-induced obese mice. in the present study, GS inhibited the appetite, reduced the body weight, visceral fat, body fat content and blood glucose, and ameliorated the glucose tolerance of the obese mice compared with HFd mice. in addition, the levels of aspartate aminotransferase and alanine aminotransferase, triglyceride (TG), leptin and insulin in the serum were reduced compared with HFd mice. There was less TG in the liver, but more in the feces compared with HFd mice. using hematoxylin and eosin staining of HepG2 cells and liver tissues, GS were demonstrated to improve the non-alcoholic fatty liver of the HFd-induced obese mice and reduce the diameter of the fat cells compared with HFd mice. GS also increased oxygen consumption and carbon dioxide emissions in the metabolic cage data compared with HFd mice. in the GT1-7 cells, GS alleviated the erS induced by tunicamycin and enhanced the activation of the STaT3 phosphorylation pathway. Furthermore the erS of the liver was relieved to achieve the aforementioned pharmacological effects. GS were used in the homeostatic control of the energy and lipid metabolism of a diet-induced obesity model. in conclusion, present studies suggest that GS exert these effects by increasing STaT3 phosphorylation expression and reducing the erS. Thus, GS reduce body weight and ameliorate hepatic steatosis in HFd-induced obese mice.

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“…Activated PPARα pathways lead to increased fatty acid oxidation 35 and energy burning, 36 which may explain small, but nevertheless significant weight loss in mice treated with high doses of IVA337. Another concern with antifibrotic agents is whether, via their mode of action, they could interfere with the wound equilibrium.…”

Section: Discussionmentioning

confidence: 99%

Pan PPAR agonist IVA337 is effective in prevention and treatment of experimental skin fibrosis

et al. 2016

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BackgroundThe pathogenesis of systemic sclerosis (SSc) involves a distinctive triad of autoimmune, vascular and inflammatory alterations resulting in fibrosis. Evidence suggests that peroxisome proliferator-activated receptors (PPARs) play an important role in SSc-related fibrosis and their agonists may become effective therapeutic targets.ObjectiveTo determine the expression of PPARs in human fibrotic skin and investigate the effects of IVA337, a pan PPAR agonist, in in vitro and in vivo models of fibrosis.MethodsThe antifibrotic effects of IVA337 were studied using a bleomycin-induced mouse model of dermal fibrosis. The in vivo effect of IVA337 on wound closure and inflammation were studied using an excisional model of wound healing.ResultsLow levels of PPARα and PPARγ were detected in the skin of patients with SSc compared with controls. In mice, IVA337 was associated with decreased extracellular matrix (ECM) deposition and reduced expression of phosphorylated SMAD2/3—intracellular effector of transforming growth factor (TGF)-β1. Although the antifibrotic effect of pan PPAR was similar to that of PPARγ agonist alone, a significant downregulation of several markers of inflammation was associated with IVA337. Despite its anti-inflammatory and antifibrotic properties, IVA337 did not interfere with wound closure. In vitro effects of IVA337 included attenuation of transcription of ECM genes and alteration of canonical and non-canonical TGF-β signalling pathways.ConclusionsThese findings indicate that simultaneous activation of all three PPAR isoforms exerts a dampening effect on inflammation and fibrosis, making IVA337 a potentially effective therapeutic candidate in the treatment of fibrotic diseases including SSc.

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PPARα-Deficient ob/ob Obese Mice Become More Obese and Manifest Severe Hepatic Steatosis Due to Decreased Fatty Acid Oxidation

Abstract: 2016-11-02T18:49:00

Cited by 76 publications

References 58 publications

Obesity and steatosis promotes mitochondrial remodeling that enhances respiratory capacity in the liver of ob/ob mice

Obesity and steatosis promotes mitochondrial remodeling that enhances respiratory capacity in the liver of ob/ob mice

Ginsenosides reduce body weight and ameliorate hepatic steatosis in high fat diet‑induced obese mice via endoplasmic reticulum stress and p‑STAT3/STAT3 signaling

Pan PPAR agonist IVA337 is effective in prevention and treatment of experimental skin fibrosis

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