Chronic systemic exposure to IL6 leads to deregulation of glycolysis and fat accumulation in the zebrafish liver

Singh, Manoj Kumar; Jayarajan, Rijith; Varshney, Swati; Upadrasta, Sindhuri; Singh, Archana; Yadav, Rajni; Scaria, Vinod; Sengupta, Shantanu; Shanmugam, Dhanasekaran; Shalimar, S.; Sivasubbu, Sridhar; Gandotra, Sheetal; Sachidanandan, Chetana

doi:10.1016/j.bbalip.2021.158905

Cited by 14 publications

(33 citation statements)

References 49 publications

(47 reference statements)

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“…2C). These patterns of gene expression were very similar to those observed in the IL6-OE adult liver (9). In our previous study the adult liver of IL6-OE zebrafish had also shown down regulation of autophagy genes.…”

Section: Suppression Of Lipogenesis Cholesterol Metabolism β-Oxidatio...supporting

confidence: 83%

“…In all NAFLD models studied, excessive accumulation of neutral lipid, especially triglycerides in the liver, is associated with dysregulation of glucose and lipid metabolism that leads to inflammation and further deterioration of the liver leading to fibrosis and cirrhosis(10). In the inflammation-induced fatty liver model in zebrafish we found dysregulated expression of glycolytic and lipid metabolism genes, but the pattern was distinct from the high fat/fructose diet models(9).…”

Section: Introductionmentioning

confidence: 72%

“…Since, our previous study has shown that IL6-OE fish accumulates fat in the liver(9), we used Oil red O (ORO) stain to detect fat accumulation in liver in the zebrafish larvae and found that at 5dpf there was no significant difference between control and IL6-OE. However, by 7dpf there was a clear increase in hepatic fat as well as liver size in the IL6-OE larvae compared to the control.…”

Section: Resultsmentioning

confidence: 99%

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A diet-independent zebrafish model for NAFLD recapitulates patient lipid profiles and offers a system for small molecule screening

Singh

Yadav

Bhaskar

et al. 2022

Preprint

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Non-alcoholic Fatty Liver Disease (NAFLD) or pathological hepatic lipid overload, is considered to affect obese individuals. However, NAFLD in lean individuals is prevalent, especially in South Asian population. The pathophysiology of lean NAFLD is not well understood and most animal models of NAFLD use the high-fat diet paradigm. To bridge this gap, we have developed a diet-independent model of NAFLD in zebrafish. We have previously showed that chronic systemic inflammation causes metabolic changes in the liver leading to hepatic fat accumulation in an IL6 overexpressing (IL6-OE) zebrafish model. In the present study, we compared the hepatic lipid composition of adult IL6-OE zebrafish to the controls and found an accumulation of saturated triacylglycerols and a reduction in the unsaturated triacylglycerol species reminiscent of NAFLD patients. Zebrafish is an ideal system for chemical genetic screens. We tested whether the hepatic lipid accumulation in the IL6-OE is responsive to chemical treatment. We found that PPAR-gamma agonist Rosiglitazone, known to reduce lipid overload in the high fat diet models of NAFLD, could ameliorate the fatty liver phenotype of the IL6-OE fish. Rosiglitazone treatment reduced the accumulation of saturated lipids and showed a concomitant increase in unsaturated TAG species in our inflammation-induced NAFLD model. Our observations suggest that the IL6-OE model can be effective for small molecule screening to identify compounds that can reverse hepatic lipid accumulation, especially relevant to lean NAFLD.

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Section: Suppression Of Lipogenesis Cholesterol Metabolism β-Oxidatio...supporting

confidence: 83%

Section: Introductionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

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A diet-independent zebrafish model for NAFLD recapitulates patient lipid profiles and offers a system for small molecule screening

Singh

Yadav

Bhaskar

et al. 2022

Preprint

Self Cite

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“…Like obesity-related NAFLD, lean individuals with NAFLD present decreased levels of adiponectin, an important hormone with insulin-sensitizing and anti-inflammatory effects [32,33]. Additionally, results from animal models reveal that interleukin 6 (IL-6) overexpression may not only be a consequence but also a central causal factor of NAFLD regardless of the presence of overweight/obesity [34]. Other potential cytokines involved in lean/non-obese NAFLD development are shown in Figure 1.…”

Section: Visceral Fat and Metabolic Dysfunctionmentioning

confidence: 99%

Non-Alcoholic Fatty Liver Disease in Lean and Non-Obese Individuals: Current and Future Challenges

et al. 2021

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Non-alcoholic fatty liver disease (NAFLD), which approximately affects a quarter of the world’s population, has become a major public health concern. Although usually associated with excess body weight, it may also affect normal-weight individuals, a condition termed as lean/non-obese NAFLD. The prevalence of lean/non-obese NAFLD is around 20% within the NAFLD population, and 5% within the general population. Recent data suggest that individuals with lean NAFLD, despite the absence of obesity, exhibit similar cardiovascular- and cancer-related mortality compared to obese NAFLD individuals and increased all-cause mortality risk. Lean and obese NAFLD individuals share several metabolic abnormalities, but present dissimilarities in genetic predisposition, body composition, gut microbiota, and susceptibility to environmental factors. Current treatment of lean NAFLD is aimed at improving overall fitness and decreasing visceral adiposity, with weight loss strategies being the cornerstone of treatment. Moreover, several drugs including PPAR agonists, SGLT2 inhibitors, or GLP-1 receptor agonists could also be useful in the management of lean NAFLD. Although there has been an increase in research regarding lean NAFLD, there are still more questions than answers. There are several potential drugs for NAFLD therapy, but clinical trials are needed to evaluate their efficacy in lean individuals.

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“…Zebrafish has been used very successfully in studying liver development and diseases that affect the liver such as hereditary liver diseases [13], biliary defects [14,15], fatty liver diseases [16] and hepatocellular carcinoma [17,18]. We have previously characterized a cell-ablation model for liver damage and regeneration in the adult zebrafish [19].…”

Section: Introductionmentioning

confidence: 99%

BML-257, a small molecule that protects against drug induced liver injury in zebrafish

Jagtap

Basu

Lokhande

et al. 2022

Preprint

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The use of many essential drugs is restricted due to their deleterious effects on the liver. Molecules that can prevent or protect the liver from drug induced liver injury (DILI) would be valuable in such situations. We used hepatocyte-specific expression of bacterial nitroreductase in zebrafish to cause temporally controlled liver damage. This transgenic line was used to run a whole organism based chemical screen in zebrafish larvae. In this screen we identified BML-257, a potent small molecule AKT inhibitor, that protected the liver against metronidazole-induced liver injury. BML-257 also showed potent prophylactic and pro-regenerative activity in this liver damage model. BML-257 also showed remarkable protective action in two independent toxicological models of liver injury caused by acetaminophen and Isoniazid. This suggests that BML-257 may have the potential to protect against multiple kinds of drug induced liver injury.

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Chronic systemic exposure to IL6 leads to deregulation of glycolysis and fat accumulation in the zebrafish liver

Cited by 14 publications

References 49 publications

A diet-independent zebrafish model for NAFLD recapitulates patient lipid profiles and offers a system for small molecule screening

A diet-independent zebrafish model for NAFLD recapitulates patient lipid profiles and offers a system for small molecule screening

Non-Alcoholic Fatty Liver Disease in Lean and Non-Obese Individuals: Current and Future Challenges

BML-257, a small molecule that protects against drug induced liver injury in zebrafish

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