As a treatment for dyslipidemia, oral doses of 1-3 grams of nicotinic acid per day lower serum triglycerides, raise high density lipoprotein cholesterol, and reduce mortality from coronary heart disease ( Tavintharan

Ethanol is a tumor promoter and may enhance the metastasis of breast cancer. We have previously demonstrated that over-expression of ErbB2 promoted ethanol-mediated invasion of mammary epithelial cells and breast cancer cells. However, the underlying cellular/molecular mechanisms remain unknown. By gelatin zymography, we showed that over-expression of ErbB2 increased the production of matrix metalloproteinase-2 (MMP-2) and MMP-9 in human mammary epithelial cells (HB2). Transient or stable transfection of ErbB2 cDNA to HB2 cells upregulated the transcripts and the activity of the MMP-2/-9 gene promoter; the upregulation of MMP-2/-9 expression was mediated by p38 mitogen-activated protein kinase (p38 MAPK) and phosphatidylinositol 3-kinase (PI3K). Although ethanol, at physiologically relevant concentrations (100-400 mg/dl), did not affect the production of MMP-2/-9, it activated MMP-2 in HB2 cells over-expressing ErbB2 (HB2 Key words: alcohol; ErbB; metastasis; proteinases; signal transduction; oxidative stress Breast cancer is a leading cause of morbidity and mortality in women.1 The endogenous and environmental factors that contribute to its etiology remain elusive. Alcohol is a tumor promoter; there is a positive correlation between heavy alcohol intake and the risk of breast cancer.2-4 Epidemiological studies reveal that alcohol consumption is associated with advanced and invasive breast tumors, [5][6][7] suggesting that alcohol may enhance tumor development and metastasis. These epidemiological results are supported by experimental studies using animal models and cell culture systems, which consistently show that ethanol promotes mammary tumorigenesis and stimulates proliferation, as well as the invasion of breast cancer cells. [8][9][10][11][12][13][14][15][16] The molecular mechanisms underlying ethanol action, however, remain to be determined.The ErbB family of receptor kinases includes 4 closely related members: epidermal growth factor receptor (EGFR or ErbB1), ErbB2, ErbB3 and ErbB4. Among the family, ErbB2 is most directly related to breast cancer. Amplification of ErbB2 is found in 20-30% of breast cancer patients and is associated with poor prognosis.17 Over-expression of ErbB2 is positively correlated with lymph node metastasis in breast cancer patients. 18,19 Although no known ligand has been identified, ErbB2 is the preferred heterodimerization partner for all ErbB family members, and it plays a pivotal role in intracellular signaling mediated by other ErbB receptors. 20 The status of ErbB2 expression in a given cell is critical in determining the cellular response to growth factors or environmental stimuli. [21][22][23] We have previously shown that over-expression of ErbB2 dramatically promoted ethanol-induced invasion of mammary epithelial cells and breast tumor cells.12 The present study was designed to determine the underlying molecular mechanisms.The metastasis of cancer cells involves multiple steps. Tumor cells must first detach from the tumor mass and invade the surrounding extracellular m...

Together, these studies show that Angptl3 is transcriptionally regulated by LXR, and reveals a novel mechanism by which LXR may regulate lipid metabolism.-Kaplan, R

ATP-binding cassette transporter A1 (ABCA1) mediates an active efflux of cholesterol and phospholipids and is mutated in patients with Tangier disease. Expression of ABCA1 may be increased by certain oxysterols such as 22(R)-hydroxycholesterol via activation of the nuclear hormone receptor liver X receptor (LXR). In searching for potential modulators of ABCA1 expression, we have studied the effects of various mevalonate metabolites on the expression of ABCA1 in two human cell lines, THP-1 and Caco-2 cells. Most of the tested metabolites, including mevalonate, geranyl pyrophosphate, farnesyl pyrophosphate, and ubiquinone, failed to significantly change the expression levels of ABCA1. However, treatment with geranylgeranyl pyrophosphate resulted in a dose-and time-dependent reduction of ABCA1 expression. Geranylgeranyl pyrophosphate appears to reduce ABCA1 expression via two different mechanisms. One of these mechanisms is by acting directly as an antagonist of LXR since it reduces the interaction between LXR␣ or -␤ with nuclear coactivator SRC-1. Another mechanism appears to involve activation of the Rho GTP-binding proteins since treatment of Caco-2 cells with inhibitors of geranylgeranyl transferase or the Rho proteins significantly increased the expression and promoter activity of ABCA1. Further studies showed that mutations in the DR4 element of the ABCA1 promoter completely eliminate the inducible activities of these inhibitors. These data indicate that activation of the Rho proteins may change the activation status of LXR.Plasma concentration of high density lipoprotein cholesterol is inversely related to the incidence of coronary heart disease (1, 2). Our understanding of the mechanisms that regulate HDL 1 cholesterol has received a major advance with the elucidation of the cause of Tangier disease (TD). Patients with TD are characterized by near or complete absence of circulating HDL and by the accumulation of cholesteryl esters in many peripheral tissues (3, 4). Recently three groups independently reported identification of the ATP-binding cassette transporter A1 (ABCA1) as the defective gene responsible for TD (5-7). ABCA1 is a member of the ATP-binding cassette superfamily. These proteins couple the energy provided by ATP hydrolysis to the transport of a wide variety of molecules across membranes (8 -11). ABCA1 is thought to mediate the active efflux of cholesterol and phospholipids to apolipoprotein (apo) acceptors, most importantly apoA-I, the major apo of HDL (12, 13). Due to mutations, however, the function of ABCA1 in patients with TD is impaired. Therefore, cellular cholesterol efflux in TD patients is defective, which leads to accumulation of excess cellular cholesterol and defective formation of HDL (14 -16). ABCA1 is widely expressed and is particularly abundant in monocytes and macrophages (17). Studies in macrophages haveshown that the expression of ABCA1 is sterol-dependent (17). Expression of ABCA1 is up-regulated by modified low density lipoprotein and down-regulated by HDL (17, 18). The ...

The development of the cerebellar cortex depends on intrinsic genetic programs and orchestrated cell-cell/cell-matrix interactions. Matrix metalloproteinases (MMPs) are proteolytic enzymes that play an important role in these interactions. MMP-2 and MMP-9 are involved in diverse neuronal functions including migration, process extension, and synaptic plasticity. We investigated the spatiotemporal pattern of expression/activity of MMP-2/MMP-9 in the developing cerebellum and their role in the histogenesis of the cerebellar cortex. The levels of transcripts of MMP-2/MMP-9 were measured with real-time quantitative polymerase chain reaction. An initial decrease in MMP-2/MMP-9 transcripts was observed between postnatal days 3 (PD3) and PD6, and the mRNA levels remained relatively constant thereafter. Zymographic analysis revealed that the expression/activity of MMP-2/MMP-9 persisted longer than their transcripts; the downregulation occurred around PD9, suggesting a mechanism of translational or post-translational regulation. The gelatinase activity was localized in the external granule layer (EGL) and the internal granule layer during PD3-PD12. The immunoreactivity of MMP-2 was mainly localized in the EGL, the Bergmann glial fibers, and the Purkinje cell layer (PCL), whereas MMP-9 immunoreactivity was detected intensively in the PCL and the extracellular space of the molecular layer. Expression of MMP-9 was relatively weak in the EGL. The immunoreactivity of MMP-2/MMP-9 became undetectable after PD21. A similar expression pattern of MMP-2/MMP-9 was observed in organotypic cerebellar slice cultures. Exposure of organotypic slices to a specific MMP-2/MMP-9 inhibitor significantly increased the thickness of the EGL and concurrently decreased the number of migrating granule neurons in the molecular layer. Thus, MMP-2 and MMP-9 play a role in the postnatal cerebellar morphogenesis.

Phenolic acids are found in abundance throughout the plant kingdom. Consumption of wine or other rich sources of phenolic acids, such as the "Mediterranean diet," has been associated with a lower risk of cardiovascular disease. The underlying mechanism(s), however, has remained unclear. Here, we show that many phenolic acids, including those from the hydroxybenzoic and hydroxycinnamic acid classes, can bind and activate GPR109A (HM74a/PUMA-G), the receptor for the antidyslipidemic agent nicotinic acid. In keeping with this activity, treatment with a number of phenolic acids, including cinnamic acid, reduces lipolysis in cultured human adipocytes and in fat pats isolated from wild-type mice but not from mice deficient of GPR109A. Oral administration of cinnamic acid significantly reduces plasma levels of FFA in the wild type but not in mice deficient of GPR109A. Activation of GPR109A by phenolic acids may thus contribute to a cardiovascular benefit of these plant-derived products.-Ren, N

No abstract

Two ATP-binding cassette transporter proteins, ABCA1 and ABCG1, may mediate an active efflux of cellular cholesterol and phospholipids. They are ubiquitously expressed and are subject to regulation by cholesterol loading or by treatment with agents that activate the nuclear hormone receptor LXR. Earlier studies in both primates and non-primates reported that treatment with endotoxin (bacterial lipopolysaccharide, LPS) reduces plasma levels of HDL cholesterol. To determine if such HDL reduction correlates with a change in ABCA1 or ABCG1 expression, their expressions were measured in THP-1 monocytes and mice treated with LPS. LPS treatment leads to a rapid, dosedependent increase of ABCA1 but not ABCG1 mRNA expression. Analysis of mouse livers showed that LPS treatment decreases expression of CYP7A, another target gene of LXR. When THP-1 cells were transfected with the ABCA1 promoter construct ( ؊ 928 to ؉ 101 bp), promoter activity was significantly increased by treatment of 22( R )hydroxycholesterol but not by LPS. Together, these studies show that LPS regulates ABCA1 expression through an LXR-independent mechanism. Further studies showed that treatment with Rhodobacter sphaeroiders LPS, an LPS antagonist, or PD169316, a specific p38 MAP kinase inhibitor, prevented the induction of ABCA1 by LPS. Therefore, this suggests that both transport of LPS from the plasma membrane to an intracellular site and activation of p38 MAP kinase are involved in the LPS-mediated induction of ABCA1. -Kaplan, R., X. Gan, J. G. Menke, S. D Wright, and T-Q. Cai. Bacterial lipopolysaccharide induces expression of ABCA1 but not ABCG1 via an LXR-independent pathway.