Fibrosis in alcoholic and nonalcoholic steatohepatitis

Both alcoholic and nonalcoholic steatohepatitis are relevant causes of cirrhosis and liver-related mortality. Alcohol abuse represents a major health problem in many countries, and liver disease is considered one of the most relevant causes of death related to this factor. Nonalcoholic fatty liver disease is the most common hepatic abnormality in the Western world, and progresses to cirrhosis and hepatocellular carcinoma in a significant portion of cases. Moreover, presence of NAFLD is associated with an increased risk of cardiovascular events. In this review, we discuss the characteristics of fibrosis in alcoholic and nonalcoholic steatohepatitis, focussing on the diagnostic issues and predictive factors. In addition, the pathogenetic mechanisms responsible for appearance and progression of fibrosis in the two conditions are briefly discussed.     

脂肪细胞中甘油三酯代谢的研究进展

脂肪组织不仅是能量储存器官.而且是参与能最代谢及肥胖相关疾病发生的内分泌器官.脂肪细胞内脂质代谢异常及脂肪组织功能失调与许多疾病的发生、发展密切相关.理解脂肪细胞内脂质代谢的分子过程及调控将为肥胖相关疾病的治疗提供新靶点.现主要从脂滴的结构与功能、脂滴内甘油三酯代谢以及与脂质代谢密切相关的脂肪酶、脂肪细胞因子和信号通路等方面进行综述.     

Pharmacological effects of lipid-lowering drugs on circulating adipokines

The cardioprotective effects of lipid-lowering drugs have been primarily attributed to their effects on blood lipid metabolism. However, emerging evidence indicates that lipid-lowering drugs also modulate the synthesis and secretion of adipose tissue-secreted proteins referred to as adipokines. Adipokines influence energy homeostasis and metabolism and have also been shown to modulate the vascular inflammatory cascade. The purpose of this review will be to examine the reported effects of commonly used lipid-lowering drugs (statins, fibrates, niacin and omega-3-fatty acids) on the circulating concentrations of leptin, adiponectin, tumor necrosis-factor-α (TNF-α), Retinol binding protein 4 (RBP4) and resistin. Overall, the lipid-lowering drugs reviewed have minimal effects on leptin and resistin concentrations.Conversely, circulating adiponectin concentrations are consistently increased by each lipid-lowering drug reviewed with the greatest effects produced by niacin. Studies that have examined the effects of statins, niacin and omega-3-fatty acids on TNF-α demonstrate that these agents have little effect on circulating TNF-α concentrations. Niacin and fibrates appear to lower RBP4 but not resistin concentrations. The results of the available studies suggest that a strong relationship exists between pharmacological reductions in blood lipids and adiponectin that is not obvious for other adipokines reviewed.     

Acute and prolonged effects of TNF-α on the expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture

The pro-inflammatory cytokine TNF-α has multiple effects on adipocyte function, including the production of adipokines. In this paper, we have examined the acute vs prolonged effects of TNF-α on the expression and secretion of key inflammation-related adipokines by human adipocytes. Adipocytes differentiated in culture were treated with TNF-α for 1–24 h, mRNA quantitated by real-time polymerase chain reaction (PCR) and secreted adipokines by ELISA. Treatment of adipocytes with TNF-α for up to 24 h had little effect on MIF, MT-2 and PAI-1 mRNA levels. TNF-α decreased adiponectin, adipsin, haptoglobin and leptin mRNA levels by 24 h, but adiponectin and haptoglobin mRNA was initially increased. In contrast, TNF-α induced rapid and substantial increases in expression of the genes encoding IL-6, MCP-1, NGF and TNF-α itself; IL-6 and TNF-α mRNA levels peaked at 2 h with 75-fold and 600-fold increases, respectively. The elevated MCP-1, NGF and VEGF mRNA levels were sustained between 4 and 24 h. The adipokine secretion pattern largely paralleled cellular mRNA levels; IL-6 (transiently), MCP-1, NGF and VEGF release were stimulated by TNF-α, with an accelerating rate of MCP-1 secretion over 24 h. TNF-α has rapid and substantial effects on the synthesis of key inflammation-related adipokines in human adipocytes, with highly gene-specific responses.     

Decreased levels of plasma adiponectin associated with increased risk of colorectal cancer

AIM:To investigate the association between adiponectin levels and risk of colorectal adenoma and cancer (early and advanced).METHODS: A cross-sectional study in a cohort of hospital-based patients was conducted between January 2004 and March 2006 at Yamagata University Hospital. Male subjects, who had colorectal tumors detected by endoscopic examination, were enrolled according to inclusion and exclusion criteria. Based on the T factor of the TNM system, intraepithelial carcinoma and submucosally invasive c...     

GW4064, a farnesoid X receptor agonist,upregulates adipokine expression in preadipocytes and HepG2 cells

AIM: To investigate the effect of GW4064 on the expression of adipokines and their receptors during differentiation of 3T3-L1 preadipocytes and in HepG2 cells.METHODS: The mRNA expression of farnesoid X receptor (FXR), peroxisome proliferator-activated receptor-gamma 2 (PPAR-γ2), adiponectin, leptin, resistin, adiponectin receptor 1 (AdipoR1), adiponectin receptor 2 (AdipoR2), and the long isoform of leptin receptor (OB-Rb) and protein levels of adiponectin, leptin, and resistin were determined using fluorescent real-time PCR and enzyme linked immunosorbent assay, respectively, on days 0, 2, 4, 6, and 8 during the differentiation of 3T3-L1 preadipocytes exposed to GW4064. Moreover, mRNA expression of AdipoR2 and OB-Rb was also examined using fluorescent real-time PCR at 0, 12, 24, and 48 h in HepG2 cells treated with GW4064.RESULTS: The mRNA expression of FXR, PPAR-γ2, adiponectin, leptin, resistin, AdipoR1, AdipoR2, and OB-Rb and protein levels of adiponectin, leptin, and resistin increased along with differentiation of 3T3-L1 preadipocytes (P < 0.05 for all). The mRNA expression of FXR, PPAR-γ2, adiponectin, leptin, and AdipoR2 in 3T3-L1 preadipocytes, and AdipoR2 and OB-Rb in HepG2 cells was significantly increased after treatment with GW4064, when compared with the control group (P < 0.05 for all). A similar trend was observed for protein levels of adipokines (including adiponectin, leptin and resistin). However, the expression of resistin, AdipoR1, and OB-Rb in 3T3-L1 cells did not change after treatment with GW4064.CONCLUSION: The FXR agonist through regulating, at least partially, the expression of adipokines and their receptors could offer an innovative way for counteracting the progress of metabolic diseases such as nonalcoholic fatty liver disease.     

Saliva as a non-invasive diagnostic tool for inflammation and insulin-resistance

Saliva has been progressively studied as a non-invasive and relatively stress-free diagnostic alternative to blood. Currently, saliva testing is used for clinical assessment of hormonal perturbations, detection of HIV antibodies, DNA analysis, alcohol screening, and drug testing. Recently, there has been increasing interest in evaluating the diagnostic potential of saliva in obesity, inflammation, and insulin-resistance. Current literature has demonstrated elevated levels of inflammatory biomarkers including C-reactive protein, tumor necrosis factor-α, interleukin-6, and interferon-γ in saliva of obese/overweight children and adults. Salivary antioxidant status has also been studied as a measure of oxidative stress in individuals with type 2 diabetes. Further, several studies have demonstrated correlations of salivary markers of stress and insulin resistance including cortisol, insulin, adiponectin, and resistin with serum concentrations. These findings suggest the potential diagnostic value of saliva in health screening and risk stratification studies, particularly in the pediatric population, with implications for inflammatory, metabolic and cardiovascular conditions. However, additionalstudies are required to standardize saliva collection and storage procedures, validate analytical techniques for biomarker detection, and establish reference ranges for routine clinical use. The purpose of this review is to summarize and evaluate recent advancements in using saliva as a diagnostic tool for inflammation and insulinresistance.     

Benefits of healthy adipose tissue in the treatment of diabetes

The major malfunction in diabetes mellitus is severe perturbation of glucose homeostasis caused by deficiency of insulin. Insulin deficiency is either absolute due to destruction or failure of pancreatic β cells, or relative due to decreased sensitivity of peripheral tissues to insulin. The primary lesion being related to insulin, treatments for diabetes focus on insulin replacement and/or increasing sensitivity to insulin. These therapies have their own limitations and complications, some of which can be life-threatening. For example, exogenous insulin administration can lead to fatal hypoglycemic episodes; islet/pancreas transplantation requires life-long immunosuppressive therapy; and anti-diabetic drugs have dangerous side effects including edema, heart failure and lactic acidosis. Thus the need remains for better safer long term treatments for diabetes. The ultimate goal in treating diabetes is to re-establish glucose homeostasis, preferably through endogenously generated hormones. Recent studies increasingly show that extra-pancreatic hormones, particularly those arising from adipose tissue, can compensate for insulin, or entirely replace the function of insulin under appropriate circumstances. Adipose tissue is a versatile endocrine organ that secretes a variety of hormones with far-reaching effects on overall metabolism. While unhealthy adipose tissue can exacerbate diabetes through limiting circulation and secreting of pro-inflammatory cytokines, healthy uninflamed adipose tissue secretes beneficial adipokines with hypoglycemic and anti-inflammatory properties, which can complement and/or compensate for the function of insulin. Administration of specific adipokines is known to alleviate both type 1 and 2 diabetes, and leptin mono-therapy is reported to reverse type 1 diabetes independent of insulin. Although specific adipokines may correct diabetes, administration of individual adipokines still carries risks similar to those of insulin monotherapy. Thus a better approach is to achieve glucose homeostasis with endogenously-generated adipokines through transplantation or regeneration of healthy adipose tissue. Our recent studies on mouse models show that type 1 diabetes can be reversed without insulin through subcutaneous transplantation of embryonic brown adipose tissue, which leads to replenishment of recipients’ white adipose tissue; increase of a number of beneficial adipokines; and fast and long-lasting euglycemia. Insulin-independent glucose homeostasis is established through a combination of endogenously generated hormones arising from the transplant and/or newly-replenished white adipose tissue. Transplantation of healthy white adipose tissue is reported to alleviate type 2 diabetes in rodent models on several occasions, and increasing the content of endogenous brown adipose tissue is known to combat obesity and type 2 diabetes in both humans and animal models. While the underlying mechanisms are not fully documented, the beneficial effects of healthy adipose tissue in improving metabolism are increasingly reported, and are worthy of attention as a powerful tool in combating metabolic disease.     

Obesity Related Adipokines and Colorectal Cancer: A Review and Meta-Analysis

Obesity has been considered as an important risk factor for the development of colorectal cancer (CRC), butthe association has not been fully elucidated. Obesity is linked significantly to adipose tissue dysfunction andto alteration of adipokines in blood; in particular, obesity-induced inflammation is thought to be an importantlink between obesity and colorectal cancer. Based on epidemiological studies, we undertook a systematic reviewto understand the association of circulating levels of selected adipokines, including adiponectin, leptin, resistin,IL-6 and TNF-α, with the level of CRC risk. Most prospective studies suggested protective effects of adiponectin,but these were attenuated by body mass index (BMI) and waist circumference (WC) data in our meta-analysis.On the other hand, meta-analyses for leptin and CRC did not demonstrate any association, similar to the resultsof systematic review. Although it proved difficult to determine whether other selected adipokines (resistin, IL-6and TNF-α) were related to CRC risk due to small number of reports, the present systematic review suggesteda positive association with elevated resistin levels but null associations with IL-6 and TNF-α.     

Effect of a high-fat diet in development of colonic adenoma in an animal model

AIM: To investigate the effect of a high-fat diet in the formation of the precursors of colorectal cancer using an animal model.METHODS: Wistar rats were divided into two groups that were fed either a high-fat diet (HFD) or a normal-fat diet (ND), and 1,2-dimethylhydrazine was administered at a dose of 40 mg/kg for 10 wk. The body weight/liver weight/epididymal fat weight were recorded after rats were sacrificed, and the formation of colonic adenoma was also observed. The levels of insulin, leptin, tumor necrosis factor (TNF)-α, insulin-like growth factor (IGF)-1 and triglycerides were determined by enzyme-linked immunosorbent assay in order to compare the altered levels of biochemical indices and inflammatory cytokines in the serum between rats fed an ND and HFD. Cell proliferation activity (Ki-67) was determined by immunohistochemical analysis. Western blot and immunofluorescence staining were used to examine the expression of proliferating cell nuclear antigen (PCNA), cyclooxygenase (COX)-2, cyclin D1, β-catenin and nuclear factor (NF)-κB proteins in the adenoma and comparative control tissues.RESULTS: The number of colonic adenomas and the colonic epithelial Ki-67 were significantly higher in the HFD group than in the ND group. The HFD group also had increased body weight, liver weight and epididymal fat weight, which were associated with increased levels of serum insulin, leptin, TNF-α, IGF-1 and triglycerides. HFD induced upregulation of PCNA, COX-2, cyclin D1, β-catenin and NF-κB proteins, as revealed by Western blot and immunofluorescence staining.CONCLUSION: HFD promotes the formation of colonic adenoma through inflammation, metabolic abnormalities, and increases cell cycle progression.