Mi-Ran Lee

Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity

AMP-activated protein kinase (AMPK) plays an important role in regulating whole body energy homeostasis. Recently, it has been demonstrated that berberine (BBR) exerts antiobesity and antidiabetic effects in obese and diabetic rodent models through the activation of AMPK in peripheral tissues. Here we show that BBR improves lipid dysregulation and fatty liver in obese mice through central and peripheral actions. In obese db/db and ob/ob mice, BBR treatment reduced liver weight, hepatic and plasma triglyceride, and cholesterol contents. In the liver and muscle of db/db mice, BBR promoted AMPK activity and fatty acid oxidation and changed expression of genes involved in lipid metabolism. Additionally, intracerebroventricular administration of BBR decreased the level of malonyl-CoA and stimulated the expression of fatty acid oxidation genes in skeletal muscle. Together, these data suggest that BBR would improve fatty liver in obese subjects, which is probably mediated not only by peripheral AMPK activation but also by neural signaling from the central nervous system.

CD137 (4–1BB) Deficiency Reduces Atherosclerosis in Hyperlipidemic Mice

Background— The tumor necrosis factor receptor superfamily, which includes CD40, LIGHT, and OX40, plays important roles in atherosclerosis. CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in human atherosclerotic lesions. However, limited information is available on the precise role of CD137 in atherosclerosis and the effects of blocking CD137/CD137 ligand signaling on lesion formation. Methods and Results— We generated CD137-deficient apolipoprotein E–knockout mice (ApoE−/−CD137−/−) and LDL-receptor–knockout mice (Ldlr−/−CD137−/−) to investigate the role of CD137 in atherogenesis. The deficiency of CD137 induced a reduction in atherosclerotic plaque lesions in both atherosclerosis mouse models, which was attributed to the downregulation of cytokines such as interferon-&ggr;, monocyte chemoattractant protein-1, and tumor necrosis factor-&agr;. CD137 signaling promoted the production of inflammatory molecules, including monocyte chemoattractant protein-1, interleukin-6, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, in endothelial cells. Stimulation of CD137 ligand signaling activated monocytes/macrophages and augmented the production of proinflammatory cytokines in atherosclerotic vessels. Conclusions— CD137/CD137 ligand signaling plays multiple roles in the progression of atherosclerosis, and thus, blockade of this pathway is a promising therapeutic target for the disease.

Peroxiredoxin 2 Deficiency Exacerbates Atherosclerosis in Apolipoprotein E–Deficient Mice

Rationale: Peroxiredoxin 2 (Prdx2), a thiol-specific peroxidase, has been reported to regulate proinflammatory responses, vascular remodeling, and global oxidative stress. Objective: Although Prdx2 has been proposed to retard atherosclerosis development, no direct evidence and mechanisms have been reported. Methods and Results: We show that Prdx2 is highly expressed in endothelial and immune cells in atherosclerotic lesions and blocked the increase of endogenous H2O2 by atherogenic stimulation. Deficiency of Prdx2 in apolipoprotein E–deficient (ApoE−/−) mice accelerated plaque formation with enhanced activation of p65, c-Jun, JNKs, and p38 mitogen-activated protein kinase; and these proatherogenic effects of Prdx2 deficiency were rescued by administration of the antioxidant ebselen. In bone marrow transplantation experiments, we found that Prdx2 has a major role in inhibiting atherogenic responses in both vascular and immune cells. Prdx2 deficiency resulted in increased expression of vascular adhesion molecule-1, intercellular adhesion molecule-1, and monocyte chemotactic protein-1, which led to increased immune cell adhesion and infiltration into the aortic intima. Compared with deficiency of glutathione peroxidase 1 or catalase, Prdx2 deficiency showed a severe predisposition to develop atherosclerosis. Conclusions: Prdx2 is a specific peroxidase that inhibits atherogenic responses in vascular and inflammatory cells, and specific activation of Prdx2 may be an effective means of antiatherogenic therapy.

Fenofibrate Differentially Regulates Plasminogen Activator Inhibitor-1 Gene Expression via Adenosine Monophosphate-Activated Protein Kinase-Dependent Induction of Orphan Nuclear Receptor Small Heterodimer Partner

Plasminogen activator inhibitor type I (PAI‐1) is a marker of the fibrinolytic system and serves as a possible predictor for hepatic metabolic syndromes. Fenofibrate, a peroxisome proliferator‐activated receptor α (PPARα) agonist, is a drug used for treatment of hyperlipidemia. Orphan nuclear receptor small heterodimer partner (SHP) plays a key role in transcriptional repression of crucial genes involved in various metabolic pathways. In this study, we show that fenofibrate increased SHP gene expression in cultured liver cells and in the normal and diabetic mouse liver by activating the adenosine monophosphate–activated protein kinase (AMPK) signaling pathway in a PPARα‐independent manner. Administration of transforming growth factor beta (TGF‐β) or a methionine‐deficient and choline‐deficient (MCD) diet to induce the progressive fibrosing steatohepatitis model in C57BL/6 mice was significantly reversed by fenofibrate via AMPK‐mediated induction of SHP gene expression with a dramatic decrease in PAI‐1 messenger RNA (mRNA) and protein expression along with other fibrotic marker genes. No reversal was observed in SHP null mice treated with fenofibrate. Treatment with another PPARα agonist, WY14643, showed contrasting effects on these marker gene expressions in wild‐type and SHP null mice, demonstrating the specificity of fenofibrate in activating AMPK signaling. Fenofibrate exhibited a differential inhibitory pattern on PAI‐1 gene expression depending on the transcription factors inhibited by SHP. Conclusion: By demonstrating that a PPARα‐independent fenofibrate‐AMPK‐SHP regulatory cascade can play a key role in PAI‐1 gene down‐regulation and reversal of fibrosis, our study suggests that various AMPK activators regulating SHP might provide a novel pharmacologic option in ameliorating hepatic metabolic syndromes. (HEPATOLOGY 2009.)

CD137-inducing factors from T cells and macrophages accelerate the destabilization of atherosclerotic plaques in hyperlipidemic mice

CD137 (4‐1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in atherosclerotic plaques, and to promote lesion formation. However, the role of CD137 in mediating atherosclerotic plaque stability and the possible underlying molecular and cellular mechanisms are poorly understood. Here, apolipoprotein E‐deficient (ApoE‐/‐) and CD137‐deficient ApoE‐/‐(ApoE‐/‐ CD137‐/‐) mice fed a chow diet for 66 wk were used. CD137 induces plaque instability, which is characterized by increased plaque necrosis, decreased collagen content, decreased vascular smooth muscle cell (VSMC) content, and increased macrophage infiltration. CD137 also increases the infiltration of effector T (Teff) cells into plaque lesion sites, resulting in increased interferon‐γ (IFN‐γ) expression. Interestingly, Teff‐cell‐derived IFN‐γ inhibits collagen synthesis in atherosclerotic plaques. Furthermore, CD137 activation increases the apoptosis of VSMCs, possibly by decreasing the antiapoptotic regulator, Bcl‐2, and subsequently up‐regulating cleaved caspase‐3. In macrophages, activation of CD137 signaling boosted the oxidized low density lipoprotein‐induced expression of matrix metalloproteinase 9 via the p38 mitogen‐activated protein kinase and extracellular signal‐regulated kinase1/2 signaling pathways. In summary, activation of CD137 signaling decreases the stability of advanced atherosclerotic plaques via its combined effects on Teff cells, VSMCs, and macrophages.—Jung, I.‐H., Choi, J.‐H., Jin, J., Jeong, S.‐J., Jeon, S., Lim, C., Lee, M.‐R., Yoo, J.‐Y., Sonn, S.‐K., Kim, Y. H., Choi, B. K., Kwon, B. S., Seoh, J.‐Y., Lee, C. W., Kim, D.‐Y., Oh, G. T. CD137‐inducing factors from T cells and macrophages accelerate the destabilization of atherosclerotic plaques in hyperlipidemic mice. FASEB J. 28, 4779–4791 (2014). www.fasebj.org

The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice.

Hyperlipidemia is a well-recognized risk factor for atherosclerosis and can be regulated by adipokines. Expression of the adipokine resistin-like molecule alpha (Retnla) is regulated by food intake; whether Retnla has a role in the pathogenesis of hyperlipidemia and atherosclerosis is unknown. Here we report that Retnla has a cholesterol-lowering effect and protects against atherosclerosis in low-density lipoprotein receptor-deficient mice. On a high-fat diet, Retnla deficiency promotes hypercholesterolaemia and atherosclerosis, whereas Retnla overexpression reverses these effects and improves the serum lipoprotein profile, with decreased cholesterol in the very low-density lipoprotein fraction concomitant with reduced serum apolipoprotein B levels. We show that Retnla upregulates cholesterol-7-α-hydroxylase, a key hepatic enzyme in the cholesterol catabolic pathway, through induction of its transcriptional activator liver receptor homologue-1, leading to increased excretion of cholesterol in the form of bile acids. These findings define Retnla as a novel therapeutic target for treating hypercholesterolaemia and atherosclerosis.

Inhibitory effects of tilianin on the expression of inducible nitric oxide synthase in low density lipoprotein receptor deficiency mice.

We investigated the effect of tilianin upon inducible nitric oxide synthesis in the plasma of low-density lipoprotein receptor knock-out (Ldlr-/-) mice fed with high cholesterol diet and in primary peritoneal macrophages of Ldlr-/- mice. High cholesterol diet induced nitric oxide production in the plasma of Ldlr-/- mice. Tilianin reduced the level of nitric oxide (NO) in plasma from Ldlr-/- mice induced by the high cholesterol diet. Tilianin also inhibited the NO production from the primary culture of peritoneal macrophages treated with lipopolysaccharide. The inhibition of NO production was caused by the suppression of inducible nitric oxide synthase (iNOS) gene expression in peritoneal macrophages isolated from Ldlr-/- mice. Moreover, tilianin inhibited the transcriptional activation of iNOS promoter that has NF-κ B binding element. Thus, these results provide the first evidence that tilianin inhibit iNOS expression and production of NO and may act as a potential anti-inflammatory agent.

Corrigendum: The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice

Nature Communications 5: Article number: 4410 (2014); Published: 15 July 2014; Updated: 21 January 2015 In the key for Fig. 4d in this Article, the labels indicating the Ldlr−/− and Ldlr−/−/Retnla-Tg groups were unintentionally placed next to the wrong symbol. The correct version of Fig. 4 appears below.