Lipopolysaccharide induces adipose differentiation-related protein expression and lipid accumulation in the liver through inhibition of fatty acid oxidation in mice

Ohhira, Masumi; Motomura, Wataru; Fukuda, Mitsuko; Yoshizaki, Takayuki; Takahashi, Nobuhiko; Tanno, Satoshi; Wakamiya, Nobutaka; Kohgo, Yutaka; Kumei, Shima; Okumura, Toshikatsu

doi:10.1007/s00535-007-2119-8

Cited by 47 publications

(35 citation statements)

References 49 publications

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“…As systemic LPS injection may not only affect monocyte programming, but also other tissues such as the liver and metabolic processes2930, we further examined whether the re-programmed monocytes, instead of other systemic effects of LPS, may be causally involved in the exacerbation of atherosclerosis. To address this issue, we performed adoptive transfer experiment with in vitro programmed monocytes.…”

Section: Resultsmentioning

confidence: 99%

The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis

et al. 2016

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Sustained low-grade inflammation mediated by non-resolving inflammatory monocytes has long been suspected in the pathogenesis of atherosclerosis; however, the molecular mechanisms responsible for the sustainment of non-resolving inflammatory monocytes during atherosclerosis are poorly understood. Here we observe that subclinical endotoxemia, often seen in humans with chronic inflammation, aggravates murine atherosclerosis through programming monocytes into a non-resolving inflammatory state with elevated Ly6C, CCR5, MCP-1 and reduced SR-B1. The sustainment of inflammatory monocytes is due to the disruption of homeostatic tolerance through the elevation of miR-24 and reduction of the key negative-feedback regulator IRAK-M. miR-24 reduces the levels of Smad4 required for the expression of IRAK-M and also downregulates key lipid-processing molecule SR-B1. IRAK-M deficiency in turn leads to elevated miR-24 levels, sustains disruption of monocyte homeostasis and aggravates atherosclerosis. Our data define an integrated feedback circuit in monocytes and its disruption may lead to non-resolving low-grade inflammation conducive to atherosclerosis.

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Section: Resultsmentioning

confidence: 99%

The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis

et al. 2016

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“…TLR4-mediated signaling in macrophages was also shown to play an important role in atherosclerosis formation (26,39). A recent in vivo study demonstrated that a single injection of LPS induced transient ADRP expression and lipid accumulation in liver in a mouse model (33). It did not, however, define the molecular mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of TLR2 and TLR4 stimulated formation of lipid bodies in leukocytes (9,37). It was shown that LPS/TLR4 mediates lipid metabolism by influencing the expression of some lipid-associated genes, upregulates sterol regulatory element-binding protein-1 and adipose fatty acid-binding protein, and downregulates scavenger receptor type B1 and PPAR␣ (10,21,22,33). In addition, it was also demonstrated using apolipoprotein E or LDL receptor knockout mice that TLR signaling, at least via TLR4 and TLR2, plays a significant role in atherosclerogenesis (26,39).…”

Section: Most Types Of Cells Store Lipid Droplets In Their Cytoplasmmentioning

confidence: 99%

Pycnogenol, an extract from French maritime pine, suppresses Toll-like receptor 4-mediated expression of adipose differentiation-related protein in macrophages

Ikuyama

Wei

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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Adipose differentiation-related protein (ADRP) is highly expressed in macrophages and human atherosclerotic lesions. We demonstrated that Toll-like receptor (TLR) 4-mediated signals, which are involved in atherosclerosis formation, enhanced the expression of ADRP in macrophages. Lipopolysaccharide (LPS) enhanced the ADRP expression in RAW264.7 cells or peritoneal macrophages from wild-type mice, but not in macrophages from TLR4-deficient mice. Actinomycin D almost completely abolished the LPS effect, whereas cycloheximide decreased the expression at 12 h, indicating that the LPS-induced ADRP expression was stimulated at the transcriptional level and was also mediated by new protein synthesis. LPS enhanced the ADRP promoter activity, in part, by stimulating activator protein (AP)-1 binding to the Ets/AP-1 element. In addition, preceding the increase of the ADRP mRNA, LPS induced the expression of interleukin (IL)-6, IL-1α, and interferon-β mRNAs, all of which stimulated the ADRP expression. Antibodies against these cytokines or inhibitors of c-Jun NH2-terminal kinase and nuclear factor (NF)-κB suppressed the ADRP mRNA level. Thus TLR4 signals stimulate the ADRP expression both in direct and indirect manners. Pycnogenol (PYC), an extract of French maritime pine, suppressed the expression of ADRP and the above-mentioned cytokines. PYC suppressed the ADRP promoter activity and enhancer activity of AP-1 and NF-κB, whereas it did not affect the LPS-induced DNA binding of these factors. In conclusion, TLR4-mediated signals stimulate the ADRP expression in macrophages while PYC antagonizes this process. PYC, a widely used dietary supplement, might be useful for prevention of atherosclerosis.

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“…Although it has been shown that several pathological or pharmacological stimuli enhance ADRP expression, the precise molecular mechanism regulating the expression is not fully elucidated. In previous studies, we and others demonstrated that an inflammatory signal, such as PMA or LPS, stimulates ADRP expression in macrophages (14,23,62), hepatocytes (46), and keratinocytes (15). We identified the Ets/AP-1 composite element in the mouse ADRP promoter and proved that it mediates, in part, the action of PMA or LPS, which enhances ADRP expression in RAW264.7 cells (23,62).…”

Section: Discussionmentioning

confidence: 99%

Oleic acid-induced ADRP expression requires both AP-1 and PPAR response elements, and is reduced by Pycnogenol through mRNA degradation in NMuLi liver cells

Fan¹,

Ikuyama²,

Gu³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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Although it is generally considered that the fatty acid effect on ADRP expression is mediated by peroxisome proliferator-activated receptors (PPARs), we identified here an additional molecular mechanism using the NMuLi mouse liver nonparenchymal cell line, which expresses PPAR␥ and ␦ but not ␣. Oleic acid (OA) and specific ligands for PPAR␥ and -␦ stimulated ADRP expression as well as the Ϫ2,090-bp ADRP promoter activity which encompasses the PPAR response element (PPRE) adjacent to an Ets/activator protein (AP)-1 site. When the AP-1 site was mutated, OA failed to stimulate the activity despite the presence of the PPRE, whereas ligands for PPAR␥ and -␦ did stimulate it and so did a PPAR␣ ligand under the coexpression of PPAR␣. DNA binding of AP-1 was stimulated by OA but not by PPAR ligands. Because we previously demonstrated that Pycnogenol (PYC), a French maritime pine bark extract, suppressed ADRP expression in macrophages partly by suppression of AP-1 activity, we tested the effect of PYC on NMuLi cells. PYC reduced the OAinduced ADRP expression along with suppression of lipid droplet formation. However, PYC neither suppressed the OA-stimulated ADRP promoter activity nor DNA binding of AP-1 but, instead, reduced the ADRP mRNA half-life. All these results indicate that the effect of OA on ADRP expression requires AP-1 as well as PPRE, and PYC suppresses the ADRP expression in part by facilitating mRNA degradation. PYC, a widely used dietary supplement, could be beneficial for the prevention of excessive lipid accumulation such as hepatic steatosis. lipid droplet; hepatic steatosis; adipose differentiation-related protein; activator protein-1; peroxisome proliferator-activated receptor CYTOSOLIC LIPID DROPLETS are physiologically important because they have specific function in various cell types or tissues, for example, as an energy reservoir in adipocytes, sites of storage and biosynthesis of eicosanoids in leukocytes, and sites of production of pulmonary surfactants in pneumocytes (44). It has been demonstrated that excessive lipid accumulation, not only in an adipose tissue but also in various nonadipose tissues, is closely related to a variety of pathological conditions, including insulin resistance, type 2 diabetes mellitus, cardiovascular diseases, and fatty liver or nonalcoholic steatohepatitis (2, 59), all of which are emerging as important clinical ands socioeconomical worldwide problems. Mechanisms of intracellular lipid droplet formation have, therefore, increasingly attracted clinical and scientific interests.A variety of proteins are associated with intracellular lipid droplets (10). Among them, PAT family proteins, which comprise perilipin, adipose differentiation-related protein (ADRP), TIP47, S3-12 and OXPAT/MLDP, are implicated in the formation, stabilization, and metabolism of lipid droplets (8, 37). ADRP was first identified in the early stages of adipocyte differentiation (33). Later studies revealed that ADRP does not directly induce adipogenesis but instead facilitates uptake of fatty ac...

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Lipopolysaccharide induces adipose differentiation-related protein expression and lipid accumulation in the liver through inhibition of fatty acid oxidation in mice

Abstract: LPS induces transient lipid accumulation and expression of ADRP in the liver through inhibition of fatty acid oxidation by downregulation of the PPARalpha-related transcriptional mechanism.

Cited by 47 publications

References 49 publications

The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis

The persistence of low-grade inflammatory monocytes contributes to aggravated atherosclerosis

Pycnogenol, an extract from French maritime pine, suppresses Toll-like receptor 4-mediated expression of adipose differentiation-related protein in macrophages

Oleic acid-induced ADRP expression requires both AP-1 and PPAR response elements, and is reduced by Pycnogenol through mRNA degradation in NMuLi liver cells

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