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Background: Biopsy is the usual gold standard for liver steatosis assessment. The aim of this study was to identify a panel of biomarkers (SteatoTest), with sufficient predictive values, for the non-invasive diagnosis of steatosis in patients with or without chronic liver disease. Biomarkers and panels were assessed in a training group of consecutive patients with chronic hepatitis C and B, alcoholic liver disease, and non-alcoholic fatty liver disease, and were validated in two independent groups including a prospective one. Steatosis was blindly assessed by using a previously validated scoring system.

Cell cycle regulators such as E2F1 and retinoblastoma (RB) play crucial roles in the control of adipogenesis, mostly by controlling the transition between preadipocyte proliferation and adipocyte differentiation. The serine-threonine kinase cyclin-dependent kinase 4 (cdk4) works in a complex with D-type cyclins to phosphorylate RB, mediating the entry of cells into the cell cycle in response to external stimuli. Because cdk4 is an upstream regulator of the E2F-RB pathway, we tested whether cdk4 was a target for new factors that regulate adipogenesis. Here we find that cdk4 inhibition impairs adipocyte differentiation and function. Disruption of cdk4 or activating mutations in cdk4 in primary mouse embryonic fibroblasts results in reduced and increased adipogenic potential, respectively, of these cells. We show that the effects of cdk4 are not limited to the control of differentiation; cdk4 also participates in adipocyte function through activation of PPARgamma.

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In addition to their role in cell cycle progression, new data reveal an emerging role of D-type cyclins in transcriptional regulation and cellular differentiation processes. Using 3T3-L1 cell lines to study adipogenesis, we observed an up-regulation of cyclin D3 expression throughout the differentiation process. Surprisingly, cyclin D3 was only minimally expressed during the initial stages of adipogenesis, when mitotic division is prevalent. This seemingly paradoxical expression led us to investigate a potential cell cycle-independent role for cyclin D3 during adipogenesis. We show here a direct interaction between cyclin D3 and the nuclear receptor peroxisome proliferator-activated receptor ␥ (PPAR␥). Our experiments reveal cyclin D3 acts as a ligand-dependent PPAR␥ coactivator, which, together with its cyclin-dependent kinase partner, phosphorylates the A-B domain of the nuclear receptor. Overexpression and knockdown studies with cyclin D3 had marked effects on PPAR␥ activity and subsequently on adipogenesis. Chromatin immunoprecipitation assays confirm the participation of cyclin D3 in the regulation of PPAR␥ target genes. We show that cyclin D3 mutant mice are protected from diet-induced obesity, display smaller adipocytes, have reduced adipogenic gene expression, and are insulin sensitive. Our results indicate that cyclin D3 is an important factor governing adipogenesis and obesity.

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The hallmarks of insulin action are the stimulation and suppression of anabolic and catabolic responses, respectively. These responses are orchestrated by the insulin pathway and are initiated by the binding of insulin to the insulin receptor, which leads to activation of the receptor's intrinsic tyrosine kinase. Severe defects in the insulin pathway, such as in types A and B and advanced type 1 and 2 diabetes lead to severe insulin resistance, resulting in a partial or complete absence of response to exogenous insulin and other known classes of antidiabetes therapies. We have characterized a novel class of arylalkylamine vanadium salts that exert potent insulin-mimetic effects downstream of the insulin receptor in adipocytes. These compounds trigger insulin signaling, which is characterized by rapid activation of insulin receptor substrate-1, Akt, and glycogen synthase kinase-3 independent of insulin receptor phosphorylation. Administration of these compounds to animal models of diabetes lowered glycemia and normalized the plasma lipid profile. Arylalkylamine vanadium compounds also showed antidiabetic effects in severely diabetic rats with undetectable circulating insulin. These results demonstrate the feasibility of insulin-like regulation in the complete absence of insulin and downstream of the insulin receptor. This represents a novel therapeutic approach for diabetic patients with severe insulin resistance. Diabetes 56: 486 -493, 2007

Peroxisome proliferator-activated receptor ␥ (PPAR␥) might not be permissive to ligand activation in prostate cancer cells. Association of PPAR␥ with repressing factors or posttranslational modifications in PPAR␥ protein could explain the lack of effect of PPAR␥ ligands in a recent randomized clinical trial. Using cells and prostate cancer xenograft mouse models, we demonstrate in this study that a combination treatment using the PPAR␥ agonist pioglitazone and the histone deacetylase inhibitor valproic acid is more efficient at inhibiting prostate tumor growth than each individual therapy. We show that the combination treatment impairs the bone-invasive potential of prostate cancer cells in mice. In addition, we demonstrate that expression of E-cadherin, a protein involved in the control of cell migration and invasion, is highly up-regulated in the presence of valproic acid and pioglitazone. We show that E-cadherin expression responds only to the combination treatment and not to single PPAR␥ agonists, defining a new class of PPAR␥ target genes. These results open up new therapeutic perspectives in the treatment of prostate cancer.Prostate cancer is the most common form of cancer in men and the second leading cause of cancer deaths. Tumor growth is originally androgen dependent. Androgens exert their effects through activation of the androgen receptor (AR), a member of the hormone nuclear receptor superfamily. In the mature prostatic gland, the AR regulates the expression of genes involved in cell division and proliferation of the epithelial cells (26). The AR is also involved in several other aspects of prostate cellular metabolism, including lipid biosynthesis, and controls the production of specialized secretory proteins with prostate-restricted expression, such as prostate-specific antigen (PSA) (26). When prostate cancer is still hormone dependent, androgen ablation therapy causes regression of the tumor (18), likely through inactivation of the transcription of the AR target genes. However, the durability of this response is inadequate and many men develop recurrent androgen-independent prostate cancer, which has a very poor prognosis (see reference 11 for a review). Other nuclear receptors or locally produced factors that interact with nuclear receptors are likely involved in cell proliferation, differentiation, and apoptosis in the prostate. The peroxisome proliferator-activated receptor ␥ (PPAR␥) is one such factor. PPAR␥ is another member of the hormone nuclear receptor superfamily. As for most of the other members of this family, its activity is regulated by ligands. Prostaglandin J2 and the antidiabetic drugs thiazolidinediones have been determined to be natural and synthetic ligands of PPAR␥, respectively (for a review, see reference 9). PPAR␥ is highly expressed in the adipose tissue and is required for its development through regulation of the expression of adipocyte-specific genes, such as lipoprotein lipase or the fatty acid transport protein aP2. PPAR␥ is expressed in several other tissues in add...