Insulin resistance caused by lipotoxicity is related to oxidative stress and endoplasmic reticulum stress in LPL gene knockout heterozygous mice

Han, Tao; Liu, Yang; Zheng, Shuang; Zhang, Yao; Liu, Wei; Hu, Yongbin

doi:10.1016/j.atherosclerosis.2015.01.020

Cited by 34 publications

(34 citation statements)

References 26 publications

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“…Lipotoxicity has been linked to the increase of oxidative stress, endoplasmic reticulum stress, inflammation, cell death, and human diseases28. Surprisingly, immune disease-related pathways (systemic lupus erythematosus and rheumatoid arthritis) appeared to be suppressed in goose fatty liver, as relevant DEGs were downregulated rather than upregulated.…”

Section: Discussionmentioning

confidence: 99%

Prosteatotic and Protective Components in a Unique Model of Fatty Liver: Gut Microbiota and Suppressed Complement System

Liu

Zhao

Wang

et al. 2016

Sci Rep

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Goose can develop severe hepatic steatosis without overt injury, thus it may serve as a unique model for uncovering how steatosis-related injury is prevented. To identify the markedly prosteatotic and protective mechanisms, we performed an integrated analysis of liver transcriptomes and gut microbial metagenomes using samples collected from overfed and normally-fed geese at different time points. The results indicated that the fatty liver transcriptome, initially featuring a ‘metabolism’ pathway, was later joined by ‘cell growth and death’ and ‘immune diseases’ pathways. Gut microbiota played a synergistic role in the liver response as microbial and hepatic genes affected by overfeeding shared multiple pathways. Remarkably, the complement system, an inflammatory component, was comprehensively suppressed in fatty liver, which was partially due to increased blood lactic acid from enriched Lactobacillus. Data from in vitro studies suggested that lactic acid suppressed TNFα via the HNF1α/C5 pathway. In conclusion, gut microbes and their hosts respond to excess energy influx as an organic whole, severe steatosis and related tolerance of goose liver may be partially attributable to gut microbiotic products and suppressed complement system, and lactic acid from gut microbiota participates in the suppression of hepatic TNFα/inflammation through the HNF1α/C5 pathway.

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Section: Discussionmentioning

confidence: 99%

Prosteatotic and Protective Components in a Unique Model of Fatty Liver: Gut Microbiota and Suppressed Complement System

Liu

Zhao

Wang

et al. 2016

Sci Rep

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“…When used in the treatment of diabetes mellitus, carvedilol increases insulin secretion, decreases the secretion of glucagon, and improves the function, proliferation and regeneration of beta cells as well as decreases their apoptosis [5,6,7,17]. Carvedilol acts on the sympathetic nervous system (SNS), which is overstimulated in diabetes mellitus, and the SNS works in tandem with the parasympathetic nervous system (PSNS) [18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Carvedilol can Replace Insulin in the Treatment of Type 2 Diabetes Mellitus

Ahmad¹

2017

J Diabetes Metab

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Introduction: A large number of patients with diabetes mellitus do not want to take insulin or any injectable medication. Carvedilol can replace insulin in the treatment of T2 diabetes mellitus. Carvedilol alone or with oral anti-diabetic drugs (OAD) can replace the entire dose of insulin for patients with T2 diabetes (T2D). Carvedilol can replace insulin in patients on OAD who need insulin. Glycemic control was achieved in patients with T2D. This study was based on the hypothesis that carvedilol decreases insulin resistance, eliminates glucotoxicity and lipotoxicty and improves the function of beta-cell while reducing their apotosis.Method: In this study, 48 patients with T2D were treated with carvedilol, which was an "off-label" use of carvedilol, for the treatment of diabetes mellitus. Twenty-nine patients with T2D were on OAD, and nineteen patients were taking insulin. Both groups had high HbA1c. Carvedilol was given with or without OAD to both groups, and glycemic control was achieved. OAD included metformin and/or glimepiride or glyburide and/or sitagliptin.Results: Glycemic control was achieved using carvedilol with or without OAD in both groups. Conclusion:1. Carvedilol can reduce insulin resistance. 2. Carvedilol can replace insulin in patients with diabetes mellitus. 3. Carvedilol and metformin can prevent the progression of pre-diabetes to diabetes. 4. Patients who are on a very high dose of insulin can decrease that dose using carvedilol and metformin.

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“…Our previous meta-analysis showed that, Asn291Ser variant in the LPL gene which is a risk factor for dyslipidemia is associated with coronary heart disease and T2DM [6]. And through animal knockout approach, we found that lipoprotein lipase knockout heterozygous (LPL+/-) mice showed dyslipidemia, impaired glucose tolerance and insulin resistance [7].…”

Section: Introductionmentioning

confidence: 97%

Fenofibrate Ameliorates Insulin Resistance of Lipoprotein Lipase Knockout Heterozygous Mice

Y¹,

Han²,

Zheng³

et al. 2020

Preprint

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Background The benefits of fenofibrate (FB), a peroxisome proliferator-activated receptor-a agonist, against hyperlipidemia have been established. We investigated the effect of fenofibrate on insulin resistance of lipoprotein lipase knockout heterozygous (LPL+/-) mice, which represent inherited hypertriglyceridemia and impaired glucose tolerance. Methods Male LPL+/- mice were treated with FB (50 mg/kg, once daily) via gavage for 8 weeks. Plasma lipid, glucose tolerance test, systemic insulin sensitivity, insulin signaling of tissues, genes and proteins related to endoplasmic reticulum (ER) stress and oxidative stress were analyzed. Results Body weight of 40-week LPL+/- with FB were reduced by 30.3% (P<0.05), while the differences of 16- and 28-week LPL+/- with FB were not significant (P>0.05). FB improved the lipid profile of both 28 and 40-week LPL+/- (P<0.001 for both), while that of 16-week LPL+/- mice with FB was unaltered (P>0.05). Glucose tolerance of 40-week LPL+/- were improved by FB (P<0.05), while that of 16- and 28-week LPL+/- with FB kept unaltered (P>0.05). Fasting insulin of 40-week LPL +/- were improved by FB (P<0.05), thus HOMA-IR of 40-week LPL+/- was declined (P<0.05). HOMA-IR of 16- and 28-week LPL+/- with FB had no change. Insulin-stimulated phosphorylated Akt (Ser473) in liver and skeletal muscle of 28-week LPL+/- was enhanced by FB (P < 0.001 and P<0.05 respectively). ER stress biomarkers were detected decreased in liver of 16- to 40-week LPL+/- with FB whereas that in muscle of LPL+/- with FB unchanged. Reduced reactive oxygen species (ROS) levels and augmented mRNA expression of superoxide dismutase (SOD) and catalase (CAT) in skeletal muscle of 28- and 40-week LPL+/- mice with FB were observed. There was no significance on ROS levels and mRNA of SOD and CAT in liver between LPL+/- mice with and without FB. Conclusions Fenofibrate improved lipid profile, glucose tolerance, systemic and tissue-specific insulin resistance of LPL knockout heterozygous mice. This may be associated with alleviated endoplasmic reticulum stress in liver and reduced oxidative stress in muscle.

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Insulin resistance caused by lipotoxicity is related to oxidative stress and endoplasmic reticulum stress in LPL gene knockout heterozygous mice

Cited by 34 publications

References 26 publications

Prosteatotic and Protective Components in a Unique Model of Fatty Liver: Gut Microbiota and Suppressed Complement System

Prosteatotic and Protective Components in a Unique Model of Fatty Liver: Gut Microbiota and Suppressed Complement System

Carvedilol can Replace Insulin in the Treatment of Type 2 Diabetes Mellitus

Fenofibrate Ameliorates Insulin Resistance of Lipoprotein Lipase Knockout Heterozygous Mice

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