Tumor Progression Locus 2 in Hepatocytes Potentiates Both Liver and Systemic Metabolic Disorders in Mice

Gong, Jun; Fang, Cheng; Zhang, Peng; Wang, Pi-Xiao; Qiu, Yixing; Shen, Lijun; Zhang, Li; Zhu, Xueyong; Shen, Tian; Li, Feng; Wang, Zhihua; Huang, Zan; Wang, Aibing; Zhang, Xiaodong; She, Zhi‐Gang

doi:10.1002/hep.29820

Cited by 16 publications

(8 citation statements)

References 49 publications

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“…Considering that NAFLD is closely associated with inflammatory response, (15) we further investigated the influence of USP10 in HFD-induced inflammatory response. After HFD treatment, the serum levels of pro-inflammatory cytokines (e.g., interleukin [IL]-1β, IL-4, IL-6, TNF-α, MCP 1, and IL-2) were significantly higher in USP10-KO mice than in WT mice, but the level of the anti-inflammatory factor (IL-10) was lower in USP10-KO mice (Fig.…”

Section: Usp10 Deficiency Aggravates Hfd-induced Hepatic Steatosis Anmentioning

confidence: 99%

Ubiquitin‐Specific Peptidase 10 (USP10) Inhibits Hepatic Steatosis, Insulin Resistance, and Inflammation Through Sirt6

Luo

Qin²,

Zhu

et al. 2018

Hepatology

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Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance and inflammation, and the pathogenic mechanism of NAFLD is poorly understood. Ubiquitin-specific peptidase 10 (USP10), a member of the ubiquitin-specific protease family, is involved in environmental stress responses, tumor growth, inflammation, and cellular metabolism. However, the role of USP10 in hepatic steatosis, insulin resistance, and inflammation remains largely unexplored. USP10 expression was detected in livers of patients with NAFLD, mice with high-fat diet (HFD)-induced obesity, and genetically obese (ob/ob) mice, as well as in palmitate-induced hepatocytes. The function of USP10 in hepatic steatosis, insulin resistance, and inflammation was investigated using hepatocyte-specific USP10 deficiency or overexpression in mice induced by HFD treatment or genetic defect. The molecular mechanisms underlying USP10-regulated hepatic steatosis were further investigated in HFD-treated mice. USP10 expression was significantly decreased in the fatty livers of NAFLD patients and obese mice and in palmitate-treated hepatocytes. USP10 deficiency exacerbated the metabolic dysfunction induced by HFD treatment for 12 weeks. Conversely, USP10 overexpression significantly suppressed metabolic dysfunction in mice after HFD treatment and inhibited the development of NAFLD in ob/ob mice. Further investigation indicated that USP10 regulates hepatic steatosis by interacting with Sirt6 and inhibiting its ubiquitination and degradation. Sirt6 overexpression markedly ameliorated the effects of USP10 deficiency in hepatic steatosis, insulin resistance, and inflammation. Conversely, Sirt6 deficiency decreased the ameliorative effects of USP10 overexpression in response to HFD treatment. Conclusion: USP10 inhibits hepatic steatosis, insulin resistance, and inflammation through Sirt6.

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Section: Usp10 Deficiency Aggravates Hfd-induced Hepatic Steatosis Anmentioning

confidence: 99%

Ubiquitin‐Specific Peptidase 10 (USP10) Inhibits Hepatic Steatosis, Insulin Resistance, and Inflammation Through Sirt6

Luo

Qin²,

Zhu

et al. 2018

Hepatology

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“…Another important stage of NAFLD is the inflammatory response (20). Therefore, the effect of GTP on HFD-induced inflammatory response was measured using ELISA.…”

Section: Gtp Mitigates Hfd-induced Hepatic Steatosismentioning

confidence: 99%

Green tea polyphenols attenuate hepatic steatosis, and reduce insulin resistance and inflammation in high-fat diet-induced rats

et al. 2019

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Non-alcoholic fatty liver disease (NAFLd) is characterized by hepatic steatosis, insulin resistance and inflammation; however, the exact pathogenesis of NAFLD is not fully understood. Green tea polyphenols (GTP) exhibit beneficial effects against metabolic syndrome. However, the effect of GTP on NAFLD remains largely unknown. The aim of the present study was to investigate the effects of GTP on NAFLD in high-fat diet (HFD)-induced rats. The NAFLD rat model was induced with a HFD for 8 weeks. A total of 30 adult male Sprague Dawley rats were randomly divided into three groups: i) Normal control group; ii) HFD group; and iii) HFD with GTP group. Hematoxylin and eosin and Oil Red O analyses were performed. The levels of alanine aminotransferase (ALT), aspartate amino transferase (AST) and inflammatory cytokines in the serum, as well as oxidative stress markers and hepatic lipids in the liver were measured. In addition, parameters associated with glucose metabolism were also assessed. Western blotting and RT-qPCR were used to determine the expression levels of 5' adenosine monophosphate-activated protein kinase (AMPK). HFD-induced rats exhibited features associated with NAFLD. GTP intervention significantly reduced serum ALT and AST levels. Fasting serum glucose, insulin resistance and hepatic lipid levels were all decreased in the GTP-treated rats. GTP also significantly decreased the levels of TNF-α, IL-6 and malondialdehyde. In contrast, superoxide dismutase levels were increased in the liver. Furthermore, GTP also significantly increased phosphorylation of AMPK and attenuated histopathological changes indicative of injury in liver tissue. GTP has a protective effect on HFD-induced hepatic steatosis, insulin resistance and inflammation, and the underlying mechanism may involve the AMPK pathway.

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“…The hematoxylin and eosin and oil red O staining were used to stain the hepatic tissue after C57 mice were fed with HFD for 7 weeks. 47,48 According to the abovementioned stained results, the degree of hepatic steatosis and fat deposition in mice with NAFLD are apparently higher than those in normal mice, as well as slightly higher than those in pioglitazone-treated mice (Figure 4B,C), suggesting that pioglitazone can serve as an effective drug to alleviate NAFLD. Moreover, mice fed with HFD got more body weight compared with other groups (Figure S15).…”

Section: ■ Results and Discussionmentioning

confidence: 85%

“…As reported earlier, pioglitazone is a highly selective agonist of PPARs, which can activate PPARs to regulate lipid metabolism, thereby reducing lipid and triglyceride contents in hepatocytes. , Here, pioglitazone was selected to relieve the mice with NAFLD (Figure A). The hematoxylin and eosin and oil red O staining were used to stain the hepatic tissue after C57 mice were fed with HFD for 7 weeks. , According to the abovementioned stained results, the degree of hepatic steatosis and fat deposition in mice with NAFLD are apparently higher than those in normal mice, as well as slightly higher than those in pioglitazone-treated mice (Figure B,C), suggesting that pioglitazone can serve as an effective drug to alleviate NAFLD. Moreover, mice fed with HFD got more body weight compared with other groups (Figure S15).…”

Section: Resultsmentioning

confidence: 92%

Exploring the Changes of Peroxisomal Polarity in the Liver of Mice with Nonalcoholic Fatty Liver Disease

Zhou¹,

Wu²,

Wang³

et al. 2021

Anal. Chem.

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Peroxisome proliferator-activated receptor alpha (PPAR-a) is a crucial nuclear transcription regulator of lipid metabolism, which is closely associated with the initiation and development of nonalcoholic fatty liver disease (NAFLD). Because PPAR-a can directly decide the level of peroxisomal metabolic enzymes, its changes might directly cause variations in peroxisomal polarity. Therefore, we developed a new two-photon fluorescence imaging probe, PX-P, in which the triphenylamine and cyanide moieties can real-time sense peroxisomal polarity changes. Using PX-P, we observed a prominent decrease in the peroxisomal polarity in the liver of mice with NAFLD for the first time. More importantly, we discovered that intracellular excessive peroxynitrite (ONOO–) and hydrogen peroxide (H2O2) underwent nitrification and oxidation, respectively, with various sites of PPAR-a. Interestingly, the key site of PPAR-a was nitrated by a low concentration of ONOO– rather than being oxidized by the high level of H2O2. These drastically reduced the activity of PPAR-a, accelerating the occurrence of NAFLD. Moreover, through activating PPARs with pioglitazone, peroxisomal polarity markedly increased compared with that of NAFLD. Altogether, our work presents a new approach for the early diagnosis of NAFLD and identifies potential therapeutic targets.

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Tumor Progression Locus 2 in Hepatocytes Potentiates Both Liver and Systemic Metabolic Disorders in Mice

Abstract: In hepatocytes, TPL2 acts as a key mediator that promotes both liver and systemic metabolic disturbances by specifically increasing MKK7-JNK activation. (Hepatology 2018).

Cited by 16 publications

References 49 publications

Ubiquitin‐Specific Peptidase 10 (USP10) Inhibits Hepatic Steatosis, Insulin Resistance, and Inflammation Through Sirt6

Ubiquitin‐Specific Peptidase 10 (USP10) Inhibits Hepatic Steatosis, Insulin Resistance, and Inflammation Through Sirt6

Green tea polyphenols attenuate hepatic steatosis, and reduce insulin resistance and inflammation in high-fat diet-induced rats

Exploring the Changes of Peroxisomal Polarity in the Liver of Mice with Nonalcoholic Fatty Liver Disease

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