BackgroundObesity-induced hepatic lipid accumulation causes lipotoxicity, mitochondrial dysfunction, oxidative stress, and insulin resistance, and is implicated in non-alcoholic hepatic pathologies such as steatohepatitis and fibrosis. Heme oxygenase-1 (HO-1), an important antioxidant enzyme catalyzing the rate-limiting step in heme degradation, protects against oxidative stress, inflammation, and metabolic dysregulation. Here, we demonstrate that the phytochemical, quercetin, a natural polyphenol flavonoid, protects against hepatic steatosis in obese mice fed a high-fat diet, and that it does so by inducing HO-1 and stimulating increased hepatic mitochondrial oxidative metabolism.MethodsMale C57BL/6 mice were fed a regular diet (RD), a high-fat diet (HFD), and an HFD supplemented with quercetin for 9 weeks. Levels of mitochondrial biogenesis and oxidative metabolic transcripts/proteins were measured by real-time PCR and/or Western blotting. HO-1 transcripts/proteins were measured real-time PCR and/or Western blotting.ResultsQuercetin upregulated genes involved in mitochondrial biogenesis and oxidative metabolism in lipid-laden hepatocytes and the livers of HFD-fed obese mice, and this was accompanied by increased levels of the transcription factor, nuclear erythroid 2-related factor 2 (Nrf-2), and HO-1 protein. The HO-1 inducer hemin and the HO-1 byproduct carbon monoxide (CO) also enhanced hepatic oxidative metabolism in HFD-fed obese mice. Moreover, the metabolic changes and the lipid-lowering effects of quercetin were completely blocked by the HO-1 inhibitor ZnPP and by deficiency of Nrf-2.ConclusionThese findings suggest that quercetin stimulates hepatic mitochondrial oxidative metabolism by inducing HO-1 via the Nrf-2 pathway. Quercetin may be useful in protecting against obesity-induced hepatosteatosis.

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Monocyte chemoattractant protein-1 (MCP-1) is associated with various inflammatory diseases involving bone loss, and is expressed along with its receptor by bone marrow-derived macrophages (BMM), which are osteoclast (OC) precursors. To investigate the role of MCP-1 in bone remodeling, we compared MCP-1-knockout (KO) mice with wild-type (WT) mice. The absence of MCP-1 increased bone mass and lowered serum collagen type I fragments (CTX-1) and TRACP 5b, but had no significant effect on the N-terminal propeptide of type I procollagen, suggesting that OCs are primarily responsible for the bone phenotype observed in the absence of MCP-1. MCP-1 deficiency resulted in reduced numbers and activity of OCs in vitro. It also led to a reduced level of c-Fms and receptor activator of nuclear factor-κB receptor and impaired actin ring formation. Activation of ERK, Akt, Rac1, and Rho upon M-CSF stimulation was also reduced and our evidence suggests that the aberrant actin ring formation was partly due to reduced activation of these molecules. Our findings point to a role of osteoclast MCP-1 in regulating bone remodeling. The higher bone mass in the femurs of MCP-1-KO mice could be, at least in part, due to decreased osteoclastogenesis and bone resorption resulting from aberrant M-CSF signaling in OCs.

Curcumin has anti-oxidative activity. In view of the increasing evidence for a biochemical link between increased oxidative stress and reduced bone density we hypothesized that curcumin might increase bone density by elevating antioxidant activity in some target cell type. We measured bone density by Micro-CT, enzyme expression levels by quantitative PCR or enzyme activity, and osteoclast (OC) formation by tartrate-resistant acid phosphatase staining. The bone mineral density of the femurs of curcumin-administered mice was significantly higher than that of vehicle-treated mice after ovariectomy (OVX) and this was accompanied by reduced amounts of serum collagen-type I fragments, which are markers of bone resorption. Curcumin suppressed OC formation by increasing receptor activator of nuclear factor-κB ligand (RANKL)-induced glutathione peroxidase-1, and reversed the stimulatory effect of homocysteine, a known H(2) O(2) generator, on OC formation by restoring Gpx activity. Curcumin generated an aberrant RANKL signal characterized by reduced expression of nuclear factor of activated T cells 2 (NFAT2) and attenuated activation of mitogen-activated protein kinases (ERK, JNK, and p38). Curcumin thus inhibited OVX-induced bone loss, at least in part by reducing osteoclastogenesis as a result of increased antioxidant activity and impaired RANKL signaling. These findings suggest that bone loss associated with estrogen deficiency could be attenuated by curcumin administration.

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Glucocorticoid induced tumor necrosis factor receptor (GITR) is a new member of the tumor necrosis factor^nerve growth factor receptor superfamily of which the function has not been well studied. The extracellular domain of GITR was produced in Escherichia coli and purified as a single band of predicted M r of 18.0 kDa. GITR and GITR ligand were expressed constitutively on the surface of Raw 264.7 macrophage cell line and murine peritoneal macrophages. An extracellular domain of GITR can activate murine macrophages to express inducible nitric oxide synthase and to generate nitric oxide in a dose-and time-dependent manner. ß