The Liver X Receptor Agonist T0901317 Protects Mice from High Fat Diet-Induced Obesity and Insulin Resistance

Gao, Mingming; Liu, Dexi

doi:10.1208/s12248-012-9429-3

Cited by 42 publications

(35 citation statements)

References 32 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Additionally, Laffitte et al also demonstrated that activation of LXR improved glucose tolerance in a murine model of diet-induced obesity and insulin resistance, mainly via coordinately modulating the expression of a set of genes involved in glucose metabolism (30). Consistent with these studies, our previous work demonstrated that activation of LXR by T0901317 protected mice from high-fat diet-induced insulin resistance and glucose intolerance but induced liver steatosis (29). Results summarized in this report showed that combined treatment with T0901317 and resveratrol synergistically decreased blood glucose in mice (Fig.…”

Section: Discussionsupporting

confidence: 72%

“…Activation of LXR has also been considered as a strategy for treatment of diabetes because of its involvement in glucose metabolism. We have recently shown that T0901317, a LXR activator, suppresses high-fat diet-induced obesity but induces liver steatosis (29). In the current study, we demonstrate that resveratrol suppresses T0901317-induced fat accumulation in the liver (Fig.…”

Section: Discussionsupporting

confidence: 71%

See 1 more Smart Citation

Resveratrol Suppresses T0901317-Induced Hepatic Fat Accumulation in Mice

Gao

Liu

2013

AAPS J

Self Cite

View full text Add to dashboard Cite

Abstract. Liver X receptor (LXR) has been identified as a potential target for treatment of atherosclerosis and diabetes. Activation of LXR, however, is associated with increased lipogenesis and fat accumulation in the liver. The objective of the current study was to examine the effect of resveratrol on LXR activator-induced fat accumulation in liver using mice as an animal model. Three groups of C57BL/6 mice were studied. Animals in group 1 were treated with T0901317, a potent activator of LXR in mice. Animals in group 2 served as the control and were treated with carrier solution and those in group 3 were treated with T0901317/resveratrol combination. Using histochemical and biochemical methods, we demonstrate that resveratrol treatment significantly suppressed fat accumulation in the liver induced by T0901317. In addition, resveratrol completely blocked elevation of blood levels of triglyceride and cholesterol and reduced blood glucose level. Quantitative PCR analysis revealed that resveratrol treatment did not change the mRNA levels of abca1, abcg1, cyp7a1, srebp-1c, chrebp, and acc genes compared to that of animals treated with T0901317 alone but reduced pepck and g6p gene expressions. Immunohistochemistry and Western blot analyses show resveratrol treatment activated AMP-activated protein kinase (AMPK) and increased phosphorylation of acetyl-CoA carboxylase. Treatment with T0901317 on hepatocytes increased intracellular fat accumulation and this increase was suppressed by resveratrol; the suppressive effect of resveratrol was greatly repressed by Compound C which is an inhibitor of AMPK. Collectively, these data suggest that resveratrol blocks T0901317-induced lipid accumulation in the liver and can be considered for inclusion into the treatment of diseases involving activation of liver X receptor.

show abstract

Section: Discussionsupporting

confidence: 72%

Section: Discussionsupporting

confidence: 71%

Resveratrol Suppresses T0901317-Induced Hepatic Fat Accumulation in Mice

Gao

Liu

2013

AAPS J

Self Cite

View full text Add to dashboard Cite

show abstract

“…ACLY play a crucial role in obesity-related complications in glucose and lipid homeostasis of mice liver [9]. An animal study has shown activation of LXR protection effects in obesity induced by high-fat diet [41]. In the present study, we demonstrated for the first time that cinnamon polyphenol intake significantly reduced the expression of hepatic SREBP-1c, LXRs, ACLY, and FAS.…”

Section: Discussionsupporting

confidence: 60%

Cinnamon Polyphenol Extract Inhibits Hyperlipidemia and Inflammation by Modulation of Transcription Factors in High‐Fat Diet‐Fed Rats

Tuzcu

Orhan

Şahin

et al. 2017

Oxidative Medicine and Cellular Longevity

114

View full text Add to dashboard Cite

We evaluated the effects of cinnamon polyphenol extract on hepatic transcription factors expressions including SREBP-1c and LXR-α in rats fed high fat diet (HFD). Twenty-eight Wistar rats were allocated into four groups: (i) normal control: animals fed with normal chow; (ii) cinnamon: animals supplemented with cinnamon polyphenol; (iii) HFD: animals fed a high-fat diet; and (iv) HFD + cinnamon: animals fed a high-fat diet and treated with cinnamon polyphenol. Obesity was linked to hyperglycemia, hyperlipidemia, and oxidative stress as imitated by elevated serum glucose, lipid profile, and serum and liver malondialdehyde (MDA) concentrations. Cinnamon polyphenol decreased body weight, visceral fat, liver weight and serum glucose and insulin concentrations, liver antioxidant enzymes, and lipid profile (P < 0.05) and reduced serum and liver MDA concentration compared to HFD rats (P < 0.05). Cinnamon polyphenol also suppressed the hepatic SREBP-1c, LXR-α, ACLY, FAS, and NF-κB p65 expressions and enhanced the PPAR-α, IRS-1, Nrf2, and HO-1 expressions in the HFD rat livers (P < 0.05). In conclusion, cinnamon polyphenol reduces the hyperlipidemia, inflammation, and oxidative stress through activating transcription factors and antioxidative defense signaling pathway in HFD rat liver.

show abstract

“…T0901317 was dissolved in dimethyl sulfoxide (DMSO) (50 mg/ml) and diluted (5:1) with 0.9% saline prior to injection according to prescribed protocols ( 41,(47)(48)(49). Control mice received the same solution without T0901317.…”

Section: Treatment Of Mice With Lxr Agonist T0901317mentioning

confidence: 99%

LXRα fuels fatty acid-stimulated oxygen consumption in white adipocytes

Dib

Bugge

Collins

2014

Journal of Lipid Research

View full text Add to dashboard Cite

Key hormonal regulatory mechanisms that control the balance between lipogenesis and lipolysis in adipose tissue are disrupted. Obese individuals are less sensitive to the antilipolytic actions of insulin and display an increase in basal lipolytic activity in their white adipose tissue (WAT), which results in high circulating levels of FFAs ( 6 ). These chronically elevated FFAs have been implicated in the pathogenesis of insulin resistance and type 2 diabetes ( 7 ). Thus utilization and/or sequestration of FFAs in WAT before they enter the circulation represent an important protective mechanism.The break-down of TG into FFA and glycerol in both WAT and brown adipose tissue (BAT) are largely under the control of the sympathetic nervous system (SNS) via catecholamines ( 8-10 ), and also by cardiac natriuretic peptides ( 11 ). In BAT the liberated FFAs provide not only the substrate for mitochondrial oxidative phosphorylation but they also directly activate the brown adipocyte-specifi c mitochondrial protonophoric uncoupling protein 1 (UCP1). UCP1 disengages energy stored in the proton gradient from ATP synthesis, resulting in a form of energy wastage known as thermogenesis ( 10,12 ). The existence of BAT has recently been affi rmed in adult humans ( 13,14 ). In WAT, on the other hand, it has been traditionally accepted that most of the FFAs liberated by lipolysis are released into the circulation to provide substrate for the energy requirements of other tissues in the body, including muscle, heart, and BAT ( 15, 16 ). Recent evidence, however, indicates a higher mitochondrial content in WAT than previously believed ( 17, 18 ), suggesting a greater role for white adipocyte mitochondria in the regulation of whole-body physiology ( 19 ). In addition to being released into the circulation and, to a much lesser extent, being reesterifi ed in situ ( 20 ), a portion of the liberated FFA undergoes mitochondrial oxidation within WAT itself ( 18,21,22 ). Obesity, which is characterized by an excessive increase in adipose tissue mass, is an escalating threat of epidemic proportions ( 1 ) and is highly correlated with a plethora of metabolic disorders ( 2, 3 ). Adipose tissue is a very plastic organ that can expand or contract to accommodate the needs of the organism. In cases of excess energy intake, adipose tissue engages in lipogenesis to store this energy as triglyceride (TG), while in times of inadequate dietary sources, it breaks down its reserves through lipolysis to provide substrate for oxidation and ATP synthesis within other tissues ( 4 ). Both lipogenesis and lipolysis are tightly controlled in adipocytes ( 5 ). However, in the obese condition, the normal homeostatic balance between lipogenesis and lipolysis is altered due to the excess caloric load ( 5 ). Abbreviations: AT-WT, aP2-Cre negative fl oxed (mice); ATaKO, adipose tissue LXR ␣ knockout (mice); BAT, brown adipose tissue; HFD, high-fat diet; HSL, hormone-sensitive lipase; LXR, liver X receptor; OCR, oxygen consumption rate; SNS, sympathetic nervous system...

show abstract

The Liver X Receptor Agonist T0901317 Protects Mice from High Fat Diet-Induced Obesity and Insulin Resistance

Cited by 42 publications

References 32 publications

Resveratrol Suppresses T0901317-Induced Hepatic Fat Accumulation in Mice

Resveratrol Suppresses T0901317-Induced Hepatic Fat Accumulation in Mice

Cinnamon Polyphenol Extract Inhibits Hyperlipidemia and Inflammation by Modulation of Transcription Factors in High‐Fat Diet‐Fed Rats

LXRα fuels fatty acid-stimulated oxygen consumption in white adipocytes

Contact Info

Product

Resources

About