Expression of Liver X Receptor Correlates with Intrahepatic Inflammation and Fibrosis in Patients with Nonalcoholic Fatty Liver Disease

Ahn, Sang Bong; Jang, Kiseok; Jun, Dae Won; Lee, Byung‐Hoon; Shin, Kye Jung

doi:10.1007/s10620-014-3289-x

Cited by 104 publications

(85 citation statements)

References 20 publications

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“…Three nuclear transcription factors regulating cholesterol metabolism have been linked to NAFLD: sterol regulatory element-binding protein (SREBP-2), farnesoid X receptor (FXR), and liver X receptor (LXR) [33]. LXR regulates hepatic triglyceride and cholesterol metabolism in rodents; increased expression of hepatic LXR in humans has been reported [34]; our western blotting results showed increased LXR expression in high-fat and high-cholesterol diet rat, which was reversed by perilla oil supplementation. FXR was the master regulator of bile acid synthesis [35]; it suppresses bile acid synthesis by inhibiting CYP7A1 via inducing intestinal epithelial expression of FGF15 [36]; perilla oil increased FXR expression in POH, which was inhibited in HFD.…”

Section: Discussionmentioning

confidence: 99%

Perilla Oil Supplementation Ameliorates High-Fat/High-Cholesterol Diet Induced Nonalcoholic Fatty Liver Disease in Rats via Enhanced Fecal Cholesterol and Bile Acid Excretion

Chen

Yuan

Wang

et al. 2016

BioMed Research International

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Recent experimental studies and clinical trials have shown that hepatic cholesterol metabolic disorders are closely related to the development of nonalcoholic fatty liver disease (NAFLD). The main goal of this study was to investigate the efficacy of the perilla oil rich in alpha-linolenic acid (ALA) against NASH and gain a deep insight into its potential mechanisms. Rats were fed a high-fat/high-cholesterol diet (HFD) supplement with perilla oil (POH) for 16 weeks. Routine blood biochemical tests and histological staining illustrated that the perilla oil administration improved HFD-induced hyperlipidemia, reduced hepatic steatosis, and inhibited hepatic inflammatory infiltration and fibrosis. Perilla oil also increased fecal bile acid and cholesterol excretion. Hepatic RNA-Seq analysis found that the long time perilla oil supplement notably modified the gene expression involved in cholesterol metabolism. Our results implicate that, after long-term high level dietary cholesterol feeding, rat liver endogenous synthesis of cholesterol and cholesterol-rich low density lipoprotein uptake was significantly inhibited, and perilla oil did not modulate expression of genes responsible for cholesterol synthesis but did increase cholesterol removed from hepatocytes by conversion to bile acids and increased fecal cholesterol excretion.

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Section: Discussionmentioning

confidence: 99%

Perilla Oil Supplementation Ameliorates High-Fat/High-Cholesterol Diet Induced Nonalcoholic Fatty Liver Disease in Rats via Enhanced Fecal Cholesterol and Bile Acid Excretion

Chen

Yuan

Wang

et al. 2016

BioMed Research International

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“…Higuchi et al (2008) reported that LXRa acts as one of the main regulators of lipid metabolism by regulating SREBP-1c expression in patients with NAFLD. According to our recent study investigating the association between LXRa and NAFLD in human, the positive rate of LXRa expression was 30% in control, 50% in NAFLD, and 97% in NASH group (Ahn et al, 2014). In high-fat dietinduced steatosis animal model, expression of hepatic LXRa was increased significantly from the first day of high-fat feeding that was lasted for weeks .…”

Section: Discussionmentioning

confidence: 98%

“…LXR is one of the most important regulators of de novo lipogenesis; it induces transcriptional activation of Fas, Acc, and Scd-1, both directly and indirectly, via mechanisms involving SREBP-1c and carbohydrate response element binding protein (Liang et al, 2002;Chen et al, 2004). LXRa expression levels in NAFLD patients tend to be higher than those of controls (Ahn et al, 2014). Increases in hepatic fatty acid uptake and enhanced de novo lipogenesis are of prime importance in the development of hepatic steatosis; lipid disposal via oxidation and export are only moderately affected in patients with this condition (Lewis et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Cinnamamides, Novel Liver X Receptor Antagonists that Inhibit Ligand-Induced Lipogenesis and Fatty Liver

Sim

Kim

Lee

et al. 2015

J Pharmacol Exp Ther

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Liver X receptor (LXR) is a member of the nuclear receptor superfamily, and it regulates various biologic processes, including de novo lipogenesis, cholesterol metabolism, and inflammation. Selective inhibition of LXR may aid the treatment of nonalcoholic fatty liver diseases. In the present study, we evaluated the effects of three cinnamamide derivatives on ligand-induced LXRa activation and explored whether these derivatives could attenuate steatosis in mice. N-(4-trifluoromethylphenyl) 3,4-dimethoxycinnamamide (TFCA) decreased the luciferase activity in LXRE-tkLuc-transfected cells and also suppressed ligand-induced lipid accumulation and expression of the lipogenic genes in murine hepatocytes. Furthermore, it significantly attenuated hepatic neutral lipid accumulation in a ligand-induced fatty liver mouse system. Modeling study indicated that TFCA inhibited activation of the LXRa ligand-binding domain by hydrogen bonding to Arg305 in the H5 region of that domain. It regulated the transcriptional control exerted by LXRa by influencing coregulator exchange; this process involves dissociation of the thyroid hormone receptor-associated proteins (TRAP)/DRIP coactivator and recruitment of the nuclear receptor corepressor. These results show that TFCA has the potential to attenuate ligand-induced lipogenesis and fatty liver by selectively inhibiting LXRa in the liver.

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“…LXR expression correlated with the degree of hepatic fat deposition, as well as with hepatic inflammation and fibrosis in NAFLD patients (60). Furthermore, GW3965 suppresses markers of fibrosis and stellate cell activation in primary mouse stellate cells (55).…”

Section: Role Of Nuclear Receptors In Hepatic Inflammation and Fibrosismentioning

confidence: 99%

Nuclear Receptors as Therapeutic Targets in Liver Disease: Are We There Yet?

Rudraiah

Zhang

Wang

2016

Annu. Rev. Pharmacol. Toxicol.

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Nuclear receptors (NR) are ligand-modulated transcription factors that play diverse roles in cell differentiation, development, proliferation, and metabolism and are associated with numerous liver pathologies such as cancer, steatosis, inflammation, fibrosis, cholestasis, and xenobiotic/drug-induced liver injury. The network of target proteins associated with NRs is extremely complex, comprising coregulators, small noncoding microRNAs, and long noncoding RNAs. The importance of NRs as targets of liver disease is exemplified by the number of NR ligands that are currently used in the clinics or in clinical trials with promising results. Understanding the regulation by NR during pathophysiological conditions, and identifying ligands for orphan NR, points to a potential therapeutic approach for patients with liver diseases. An overview of complex NR metabolic networks and their pharmacological implications in liver disease is presented here.

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Expression of Liver X Receptor Correlates with Intrahepatic Inflammation and Fibrosis in Patients with Nonalcoholic Fatty Liver Disease

Abstract: LXR expression correlated with the degree of hepatic fat deposition, as well as with hepatic inflammation and fibrosis in NAFLD patients. Our research suggests that LXR is an attractive target for treatment and regulation of hepatic inflammation and fibrosis.

Cited by 104 publications

References 20 publications

Perilla Oil Supplementation Ameliorates High-Fat/High-Cholesterol Diet Induced Nonalcoholic Fatty Liver Disease in Rats via Enhanced Fecal Cholesterol and Bile Acid Excretion

Perilla Oil Supplementation Ameliorates High-Fat/High-Cholesterol Diet Induced Nonalcoholic Fatty Liver Disease in Rats via Enhanced Fecal Cholesterol and Bile Acid Excretion

Cinnamamides, Novel Liver X Receptor Antagonists that Inhibit Ligand-Induced Lipogenesis and Fatty Liver

Nuclear Receptors as Therapeutic Targets in Liver Disease: Are We There Yet?

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