Elevated thyroid-stimulating hormone (TSH) and hypercholesterolemia commonly coexist, as typically seen in hypothyroidism, but there is no known mechanism directly linking the two. Here, we demonstrated that in liver cells, TSH promoted the expression of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis, by acting on the TSH receptor in hepatocyte membranes and stimulating the cyclic adenosine monophosphate / protein kinase A / cyclic adenosine monophosphate-responsive element binding protein (cAMP/PKA/CREB) signaling system. In thyroidectomized rats, the production of endogenous thyroid hormone was eliminated and endogenous TSH was suppressed through pituitary suppression with constant administration of exogenous thyroid hormone, and hepatic HMGCR expression was increased by administration of exogenous TSH. These results suggested that TSH could up-regulate hepatic HMGCR expression, which indicated a potential mechanism for hypercholesterolemia involving direct action of TSH on the liver. (HEPATOLOGY 2010;52:1401-1409 H ypothyroidism is well known to be associated with elevated serum TC, which can result in hypercholesterolemia. 1,2 The underlying mechanism is widely thought to be TH deficiency.However, elevation of serum TC has also been observed in patients with subclinical hypothyroidism (SCH), in which TSH is elevated but TH stays within its normal range. 1,3,4 Thus, the development of

Non-alcoholic fatty liver disease (NAFLD) is characterized by the aberrant accumulation of triglycerides in hepatocytes in the absence of significant alcohol consumption, viral infection or other specific causes of liver disease. NAFLD has become a burgeoning health problem both worldwide and in China, but its pathogenesis remains poorly understood. Farnesoid X receptor (FXR), a member of the nuclear receptor (NR) superfamily, has been demonstrated to be the primary sensor for endogenous bile acids, and play a crucial role in hepatic triglyceride homeostasis. Deciphering the synergistic contributions of FXR to triglyceride metabolism is critical for discovering therapeutic agents in the treatment of NAFLD and hypertriglyceridemia.

These findings indicate that YY1 plays a crucial role in obesity-associated hepatosteatosis, through repression of FXR expression.

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Highlights d Large-scale 3D electron microscopic study to reconstruct mouse cochlea neural circuits d 12% of type I SGNs show branched dendrites in adult mice d Lateral/medial olivocochlear neurons form efferent synapses on type I SGN dendrites d Efferent innervation of SGN dendrites varies with their afferent innervation

SUMMARYThe epididymis and efferent ducts play major roles in sperm maturation, transport, concentration and storage by reabsorbing water, ions and proteins produced from seminiferous tubules. Gpr48-null male mice demonstrate reproductive tract defects and infertility. In the present study, we found that estrogen receptor  (ER) was dramatically reduced in the epididymis and efferent ducts in Gpr48-null male mice. We further revealed that ER could be upregulated by Gpr48 activation via the cAMP/PKA signaling pathway. Moreover, we identified a cAMP responsive element (Cre) motif located at -1307 to -1300 bp in the ER promoter that is able to interact with Cre binding protein (Creb). In conclusion, Gpr48 participates in the development of the male epididymis and efferent ducts through regulation of ER expression via the cAMP/PKA signaling pathway. KEY WORDS: Gpr48, ER(Esr1), Creb, Epididymis, Infertility, MouseG protein-coupled receptor 48 upregulates estrogen receptor  expression via cAMP/PKA signaling in the male reproductive tract DEVELOPMENT 152 is observed in Gpr48-null mice. The expression of ER, NHE3 and aquaporin 1 (Aqp1) is reduced in the proximal segment of the efferent ducts.In the present study, we investigated the role of Gpr48 in the regulation of ER expression and further explored the molecular mechanism underlying this regulation. MATERIALS AND METHODS MiceGpr48-null male mice were housed at 21±1°C with a humidity of 55±10% and a 12-hour light-dark cycle. Food and water were available ad libitum. For genotyping analysis, genomic DNA was isolated from tail biopsy and PCR was carried out using three primers: upstream primer 5Ј-CCAGTCACCACTCTTACACAATGGCTAAAC-3Ј; and downstream primers 5Ј-GGTCTTTGAGCACCAGAGGAC-3Ј and 5Ј-TCCCGTAG -GAGATAGCGTCCTAG-3Ј. With regard to the male fertility assay, each Gpr48+/-and Gpr48 -/-adult male aged 12 weeks was housed with two Gpr48 +/+ females. The females were examined daily for vaginal plugs. The litter number was counted immediately after parturition. The animal protocol was reviewed and approved by the Animal Care Committee of Shanghai Jiao Tong University School of Medicine. Ligation operationTwenty-four mice at 3 weeks of age received bilateral efferent ductile ligation (EGL; n8), bilateral vasoligation (VGL; n8) and sham operations (n8). For EGL, the efferent ductule was doubly ligated close to the epididymis and away from the epididymal and testicular vasculature and vas deferens. For VGL, bilateral vasa deferentia were doubly ligated. The mice receiving EGL, VGL or sham operations were observed daily to ascertain a normal descending of the testes. Immunofluorescence and immunohistochemical stainingAnimal tissues were fixed overnight in Bouin's solution, dehydrated in ethanol, embedded in paraffin and sectioned at 5 m. Immunofluorescence and immunohistochemical staining were performed according to a standard protocol. In brief, the sections were de-paraffined, progressively rehydrated and treated with 3% hydrogen peroxide in methanol for 30 minutes...

Chemerin is an adipokine involved in obesity, inflammation, and innate immune system that is highly expressed in the liver. In the present study, we find that chemerin mRNA expression is decreased in the livers of rodents with nonalcoholic fatty liver disease as well as in HepG2 cells after lipid overloading. Moreover, we report that chemerin expression and secretion are induced in HepG2 cells and primary hepatocytes from wild-type mice, but not farnesoid X receptor (FXR)-/- mice, in response to the synthetic FXR ligand GW4064. Hepatic chemerin expression is decreased in FXR-/- mice but up-regulated by GW4064 administration in wild-type mice. Dual-luciferase reporter assay and chromatin immunoprecipitation analyses further identified a functional FXR response element located in the -258-bp /+121-bp region of the chemerin gene. These data demonstrate that chemerin, a novel target gene of FXR, is related to nonalcoholic steatohepatitis.

Background: The ErbB3 binding protein-1 (Ebp1) belongs to a family of DNA/RNA binding proteins implicated in cell growth, apoptosis and differentiation. However, the physiological role of Ebp1 in the whole organism is not known. Therefore, we generated Ebp1-deficient mice carrying a gene trap insertion in intron 2 of the Ebp1 (pa2g4) gene.