Hepatic TRAP80 selectively regulates lipogenic activity of liver X receptor

Kim, Geun Hyang; Oh, Gyun-Sik; Yoon, Jin Ho; Lee, Gang Gu; Lee, Ki-Up; Kim, Seung Whan

doi:10.1172/jci73615

Cited by 27 publications

(21 citation statements)

References 41 publications

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“…One recent study suggested that the hepatic LXR lipogenic program might be separated from cholesterol efflux. Silencing the LXR co-activator TRAP80 was reported to interfere with LXR-mediated induction of Srebpf1 but not Abca1 146 . However, the robust expression of Abca1 by Küpffer cells complicates the interpretation of these results.…”

Section: Introductionmentioning

confidence: 99%

Liver X receptors at the intersection of lipid metabolism and atherogenesis

2015

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Section: Introductionmentioning

confidence: 99%

Liver X receptors at the intersection of lipid metabolism and atherogenesis

2015

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“…TRAP80 was previously identified as an LXRa-interacting protein using HepG2 nuclear extracts with GST-LXRa LBD as bait (25). TRAP80 can stimulate the transcription of lipogenic genes, including SREBP-1c, but does not affect the transcription of RCT-related genes, such as ABCA1 (25).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, TRAP80 was reported to be a lipogenic coactivator in hepatocytes (25). TRAP80 is selectively recruited to the SREBP-1c promoter, but not the ABCA1 promoter.…”

Section: Recruitment Of the Coactivator Trap80 To The Srebp-1c Promotmentioning

confidence: 99%

20(S)-protopanaxatriol inhibits liver X receptor α-mediated expression of lipogenic genes in hepatocytes

Yoon

Lee

et al. 2015

Journal of Pharmacological Sciences

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20(S)-protopanaxatriol (PPT) is an aglycone of ginsenosides isolated from Panax ginseng and has several interesting activities, including anti-inflammatory and anti-oxidative stress effects. Herein, PPT was identified as an inhibitor against the ligand-dependent transactivation of liver X receptor α (LXRα) using a Gal4-TK-luciferase reporter system. LXRα is a transcription factor of nuclear hormone receptor family and stimulates the transcription of many metabolic genes, such as lipogenesis- or reverse cholesterol transport (RCT)-related genes. Quantitative RT-PCR analysis showed that PPT inhibited the LXRα-dependent transcription of lipogenic genes, such as sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase, and stearoyl CoA desaturase 1. These inhibitory effects of PPT are, at least in part, a consequence of the reduced recruitment of RNA polymerase II to the LXR response element (LXRE) of the SREBP-1c promoter. Furthermore, LXRα-dependent triglyceride accumulation in primary mouse hepatocytes was significantly reduced by PPT. Interestingly, PPT did not inhibit the LXRα-dependent transcription of ABCA1, a crucial LXRα target gene involved in RCT. Chromatin immunoprecipitation assays revealed that PPT repressed recruitment of the lipogenic coactivator TRAP80 to the SREBP-1c LXRE, but not the ABCA1 LXRE. Overall, these data suggest that PPT has selective inhibitory activity against LXRα-mediated lipogenesis, but not LXRα-stimulated RCT.

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“…Based on these studies, activation of LXRs represents an interesting therapeutic option for neurodegenerative and neuroinflammatory disorders, such as AD. However, synthetic LXR agonists show severe side-effects such as hepatic hypertriglyceridemia, resulting in liver steatosis [147]. By using cell-free and cell-based assays, multiple studies defined that plant sterols, such as sitosterol, fucosterol, stigmasterol, schottenol, 24(S)-saringosterol, and spinasterol, bind and activate LXRa and/or LXRb [46,53,[148][149][150][151].…”

Section: Phytosterols In Alzheimer's Diseasementioning

confidence: 99%

Plant sterols: Friend or foe in CNS disorders?

Vanmierlo

Bogie

Mailleux

et al. 2015

Progress in Lipid Research

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In mammals, the central nervous system (CNS) is the most cholesterol rich organ by weight. Cholesterol metabolism is tightly regulated in the CNS and all cholesterol available is synthesized in situ. Deficits in cholesterol homeostasis at the level of synthesis, transport, or catabolism result in severe disorders featured by neurological disability. Recent studies indicate that a disturbed cholesterol metabolism is involved in CNS disorders, such as Alzheimer's disease (AD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). In contrast to circulating cholesterol, dietary plant sterols, can cross the blood-brain barrier and accumulate in the membranes of CNS cells. Plant sterols are well-known for their ability to lower circulating cholesterol levels. The finding that they gain access to the CNS has fueled research focusing on the physiological roles of plant sterols in the healthy and diseased CNS. To date, both beneficial and detrimental effects of plant sterols on CNS disorders are defined. In this review, we discuss recent findings regarding the impact of plant sterols on homeostatic and pathogenic processes in the CNS, and elaborate on the therapeutic potential of plant sterols in CNS disorders.

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Hepatic TRAP80 selectively regulates lipogenic activity of liver X receptor

Abstract: Supernatants obtained from each step were stored at -70°C. For the infection of mice and mouse primary hepatocytes, Ad-293 cells were infected with crude stock virus, lysed by freezing and thawing after 24 to 48 hours, and the viruses were purified using CsCl 2 gradients.

Cited by 27 publications

References 41 publications

Liver X receptors at the intersection of lipid metabolism and atherogenesis

Liver X receptors at the intersection of lipid metabolism and atherogenesis

20(S)-protopanaxatriol inhibits liver X receptor α-mediated expression of lipogenic genes in hepatocytes

Plant sterols: Friend or foe in CNS disorders?

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