Activation of Liver X Receptors Attenuates Endotoxin-Induced Liver Injury in Mice with Nonalcoholic Fatty Liver Disease

Huang

et al. 2015

Lipids Health Dis

BackgroundIn the practical commercial pig farms, inflammation is a perennial problem, yet most of studies on inflammation are focused on immune response. Actually, inflammation can induce body metabolism disorder which will finally influence animals’ growth. In this study, we investigated the effect of acute inflammation on the triglyceride (TG) metabolism in the liver of growing pigs and the possible underlying mechanisms.MethodsTwelve male growing pigs were randomly divided into two groups, a control group (received saline) and a LPS group (intramuscular injected with 15 μg/kg LPS). Six hours after LPS injection, the pigs were euthanized and sampled. Biochemical indexes, inflammation factors, lipid metabolism related parameters and mitochondrial function were evaluated. The relationship between glucocorticoid receptor (GR) and the key enzymes of de novo lipogenesis were also investigated by chromatin immunoprecipitation assay (ChIP).ResultsLPS induced a serious inflammation in the liver of growing pigs proved by liver morphologic changes, the up-regulated plasma cortisol, tumor necrosis factor-α (TNF-α) content and gene expression of inflammation related genes in liver. For de novo lipogenesis, LPS significantly decreased the gene expression of fatty acid synthase (FAS), Acetyl-CoA carboxylase-1 (ACC-1) and Stearoyl-CoA desaturase-1 (SCD-1), and the protein expression of ACC-1 and SCD-1. For lipolysis, only the gene expression of adipose triglyceride lipase (ATGL) was decreased. LPS did nothing to the gene expression of hormone-sensitive lipase (HSL) and the lipolytic enzymes activities. For β-oxidation, LPS significantly increased the protein expression of CPT-1α, but the gene expression of mitochondrial DNA-encoded genes and the activities of mitochondrial complex IV and V demonstrated no obviously changes. Furthermore, ChIP results showed that LPS significantly decreased the level of GR binding to ACC-1 promoter.ConclusionLPS infection has a profound impact on hepatic TG metabolism. This impact is mainly demonstrated by the significantly deceased de novo lipogenesis, and GR may involve in its regulation.

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide significantly influences the hepatic triglyceride metabolism in growing pigs

Huang

et al. 2015

Lipids Health Dis

“…This study used low dose LPS (2 mg/kg, i.p. ), which has been previously shown to induce organ injury in lung [38] , kidney [39] and liver [40] . Here, we demonstrated that this low dose of LPS caused inflammation, neutrophil infiltration and histological evidence of tissue injury in lungs, liver and kidney ( Fig.…”

Section: Resultsmentioning

confidence: 91%

An Obligatory Role of NF-κB in Mediating Bone Marrow Derived Endothelial Progenitor Cell Recruitment and Proliferation Following Endotoxemic Multiple Organ Injury in Mice

Mao

et al. 2014

PLoS ONE

BackgroundRecruitment of bone marrow derived endothelial progenitor cells (BMDEPCs) alleviates multiple organ injury (MOI) and improves outcomes. However, mechanisms mediating BMDEPC recruitment following septic MOI remain largely unknown. This study characterized the kinetics of BMDEPC recruitment and proliferation and defined the role of NF-κB in regulating BMDEPC recruitment and proliferation.Methods and Main FindingsChimeric mice with an intact or disrupted NF-κB p50 gene and BMDEPC-restricted expression of green fluorescent protein were created and injected with LPS (2 mg/kg, i.p.). BMDEPC recruitment and proliferation in multiple organs were quantified. BMDEPC recruitment and proliferation are highly organ-dependent. Lungs had the highest number of BMDEPC recruitment, whereas heart, liver and kidney had only a small fraction of the number of BMDEPCs in lungs. Number of proliferating BMDEPCs was several-fold higher in lungs than in other 3 organs. Kinetically, BMDEPC recruitment into different organs showed different time course profiles. NF-κB plays obligatory roles in mediating BMDEPC recruitment and proliferation. Universal deletion of NF-κB p50 gene inhibited LPS-induced BMDEPC recruitment and proliferation by 95% and 69% in heart. However, the contribution of NF-κB to these regulations varies significantly between organs. In liver, universal p50 gene deletion reduced LPS-induced BMDEPC recruitment and proliferation only by 49% and 35%. NF-κB activities in different tissue compartments play distinct roles. Selective p50 gene deletion either in stromal/parenchymal cells or in BM/blood cells inhibited BMDEPC recruitment by a similar extent. However, selective p50 gene deletion in BM/blood cells inhibited, but in stromal/parenchymal cells augmented BMDEPC proliferation.ConclusionsBMDEPC recruitment and proliferation display different kinetics in different organs following endotoxemic MOI. NF-κB plays obligatory and organ-dependent roles in regulating BMDEPC recruitment and proliferation. NF-κB activities in different tissue compartments play distinct roles in regulating BMDEPC proliferation.

“…The activation of LXR also inhibits the expression of TNF-a and iNOS in bone marrow-derived macrophages of mice in vitro. 52 Human hepatic expression of LXRa and its related lipogenic and inflammatory genes, such as TNF-a, IL-6, osteopontin, iNOS, COX-2 and the suppressor of cytokine signaling 3 protein is abnormally increased in NAFLD and hepatitis C patients with steatosis, confirmed a potential role of LXRa in the pathogenesis of hepatic steatosis in these chronic liver diseases. 53 These data indicate that the activation of LXRa is beneficial for hepatic inflammation in hepatic steatosis.…”

Section: Lxr and Nafldmentioning

confidence: 89%

“…T0901317 administration decreases hepatic TNF‐α and iNOS expression through inhibiting c‐Jun N‐terminal kinases and the phosphatidylinositol 3‐kinase signaling pathway in the liver. The activation of LXR also inhibits the expression of TNF‐α and iNOS in bone marrow‐derived macrophages of mice in vitro 52 . Human hepatic expression of LXRα and its related lipogenic and inflammatory genes, such as TNF‐α, IL‐6, osteopontin, iNOS, COX‐2 and the suppressor of cytokine signaling 3 protein is abnormally increased in NAFLD and hepatitis C patients with steatosis, confirmed a potential role of LXRα in the pathogenesis of hepatic steatosis in these chronic liver diseases 53 .…”

Section: Introductionmentioning

confidence: 99%

Liver X receptors bridge hepatic lipid metabolism and inflammation

Qiu

2012

J of Digest Diseases

Self Cite

Liver X receptors (LXRs) are members of the superfamily of metabolic nuclear receptors, which play central roles in the regulation of cholesterol absorption, efflux, transportation and excretion and many other processes correlating with lipid metabolism. LXRs can also regulate inflammation in vitro and in vivo. Accumulating evidence demonstrates that LXR are involved in the metabolism and inflammation in human diseases. Nonalcoholic fatty liver disease (NAFLD) is classically associated with lipid metabolic disorders and inflammatory responses, especially in the nonalcoholic steatohepatitis (NASH) phase. The effects of LXRs on cholesterol metabolism and inflammation make them attractive as a potential target for the treatment of NAFLD. Since the ability to synthesize triglycerides may be protective in obesity and fatty liver, the hepatic lipogenesis by LXRs should not rule out the possibility of the use of LXRs in NAFLD.KEY WORDS: cholesterol metabolism, inflammatory response, liver X receptor, macrophage, nonalcoholic fatty liver disease.