Effectiveness of metformin for the reversal of cold-ischemia-induced damage in hepatosteatosis.

BACKGROUND: Primary dysfunction and rejection are more common in donor liver tissues with steatosis. AMP-activated protein kinase (AMPK) assumes organ-protective functions during ischemia. Metformin was used for the activation of AMPK in hepatocytes. The aim of this study is to investigate the effectiveness of metformin administration for the reversal of cold-ischemia-induced damage in hepatosteatosis. MATERIAL AND METHODS: Seven-week-old C7BL56 male-mice (n = 109) were separated into four groups depending on diet type and metformin use. A specific diet model was followed for 10 weeks to induce hepatosteatosis. A group of the animals was administered with metformin for the last four weeks via oral gavage. After resection, the liver tissues were perfused and kept for 0-6-12-24 h in the UW solution. Histopathological examinations were performed, and Western blot was utilized to analyze p-AMPK and AMPK expression levels. RESULTS: Hepatosteatosis decreased significantly with metformin. The steatotic liver group had more prominent pericentral inflammation, necrosis as well as showing a decreased and more delayed AMPK response than the non-fat group. All these alterations could be corrected using metformin. CONCLUSION: Metformin can increase the resistance of livers with hepatosteatosis to cold-ischemia-induced damage, which in turn may pave the way for successful transplantation of fatty living-donor livers.

A New Approach to Polycystic Ovary Syndrome and Related Cardio-metabolic Risk Factors: Dietary Polyphenols.

PURPOSE OF REVIEW: Polycystic ovarian syndrome (PCOS) is a common endocrine disease characterized by ovulatory dysfunction, hyperandrogenism, and polycystic ovarian morphology and causing various reproductive, metabolic, cardiovascular, oncological, and psychological complications. Recent meta-analyses and systemic reviews showed that PCOS increases the risk factor for various cardio-metabolic complications like insulin resistance, type II diabetes mellitus, dyslipidemia, metabolic syndrome, hypertension, and endothelial dysfunction. In addition to these, it was suggested that chronic low-grade inflammation and oxidative stress are the underlying mechanisms of PCOS-mediated metabolic consequences and might trigger cardio-metabolic risk in women with PCOS. At this point, there is substantial evidence to suggest that various non-nutrient food components modulate cardio-metabolic health together with inflammation and oxidative stress. RECENT FINDINGS: Increasing the intake of dietary polyphenols might reduce oxidative stress and inflammation and thus alleviate the risk of metabolic, endothelial, and cardiovascular disorders. Nowadays, there are an increasing number of studies related to the effects of dietary polyphenols on PCOS and its accompanying cardio-metabolic disturbances. Currently, there is a cumulative number of studies connected to the effects of dietary polyphenols on PCOS and accompanying cardio-metabolic disturbances. However, there is a lack of knowledge in combining the probable mechanisms of dietary polyphenols on PCOS and related cardio-metabolic consequences. Thus, the effects of dietary polyphenols on PCOS and accompanying cardio-metabolic disturbances need to be discussed and evaluated with underlying mechanisms. Consequently, this review was written to reveal the potential effects of dietary polyphenols on PCOS and related metabolic and cardiovascular risk factors in all their aspects.

Dietary fatty acids and CD36-mediated cholesterol homeostasis: potential mechanisms.

Currently, the prevention and treatment of CVD have been a global focus since CVD is the number one cause of mortality and morbidity. In the pathogenesis of CVD, it was generally thought that impaired cholesterol homeostasis might be a risk factor. Cholesterol homeostasis is affected by exogenous factors (i.e. diet) and endogenous factors (i.e. certain receptors, enzymes and transcription factors). In this context, the number of studies investigating the potential mechanisms of dietary fatty acids on cholesterol homeostasis have increased in recent years. As well, the cluster of differentiation 36 (CD36) receptor is a multifunctional membrane receptor involved in fatty acid uptake, lipid metabolism, atherothrombosis and inflammation. CD36 is proposed to be a crucial molecule for cholesterol homeostasis in various mechanisms including absorption/reabsorption, synthesis, and transport of cholesterol and bile acids. Moreover, it has been reported that the amount of fatty acids and fatty acid pattern of the diet influence the CD36 level and CD36-mediated cholesterol metabolism principally in the liver, intestine and macrophages. In these processes, CD36-mediated cholesterol and lipoprotein homeostasis might be impaired by dietary SFA and trans-fatty acids, whereas ameliorated by MUFA in the diet. The effects of PUFA on CD36-mediated cholesterol homeostasis are controversial depending on the amount of n-3 PUFA and n-6 PUFA, and the n-3:n-6 PUFA ratio. Thus, since the CD36 receptor is suggested to be a novel nutrient-sensitive biomarker, the role of CD36 and dietary fatty acids in cholesterol metabolism might be considered in medical nutrition therapy in the near future. Therefore, the novel nutritional target of CD36 and interventions that focus on dietary fatty acids and potential mechanisms underlying cholesterol homeostasis are discussed in this review.

Hepatic cholesterol synthesis and lipoprotein levels impaired by dietary fructose and saturated fatty acids in mice: Insight on PCSK9 and CD36.

OBJECTIVES: The aim of this study was to investigate the uncertain effects of high saturated fatty acids (SFAs) or fructose intake on cholesterol and lipoproteins with an insight of proprotein convertase subtilisin/kexin type 9 (PCSK9)- and cluster of differentiation 36 (CD36)-induced mechanisms. METHODS: Forty male C57 BL/6 mice (8 wks of age) were divided into four groups and fed ad libitum with standard chow or three isocaloric diets containing high SFAs (SFA group), monounsaturated fatty acids (MUFA group, vehicle), or fructose for 15 wks. Subsequently, mice were sacrificed and blood, liver, and heart were collected for further analysis. RESULTS: Consequently, fructose or SFA intake resulted in higher plasma and liver total cholesterol (TC) levels, plasma low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (HDL-C), apolipoprotein (Apo)-B levels, TC/HDL-C, and LDL-C/HDL-C ratios, and lower plasma levels of HDL-C and Apo-A1 (P < 0.05). Levels of 3-hydroxy-3-methylglutaryl-CoA reductase and acetyl-CoA acetyltransferase 1 enzymes in liver and CD36 levels in plasma were elevated by high SFAs and fructose intake (P < 0.05), whereas plasma PCSK9 levels were not significantly changed. Fructose and SFA intake increased PCSK9 and CD36 levels in the heart, along with increased CD36 levels in the liver (P < 0.05). Furthermore, plasma LDL-C was found to be positively correlated with liver PCSK9 (r = 0.85, P = 0.02), and CD36 (r = 0.70, P = 0.02) in the SFA and fructose groups. CONCLUSION: High intakes of dietary SFAs and fructose might induce dysregulations in the cholesterol synthesis and blood lipoprotein levels via proposed nutrient-sensitive biomarkers PCSK9 and CD36 in liver and extrahepatic tissues involved in cholesterol homeostasis.

The potential efficacy of dietary fatty acids and fructose induced inflammation and oxidative stress on the insulin signaling and fat accumulation in mice.

The aim of the present study was to clarify whether oxidative stress and inflammatory responses are related to impaired insulin signaling and fat accumulation induced by the dietary fatty acids and fructose. C57BL/6 type 8 week-old male mice (n = 10/per group) were fed with standard chow or three isocaloric diets consisting fructose, monounsaturated fatty acids (MUFA), or saturated fatty acid (SFA) for 15 weeks. After the dietary manipulation, the mice were sacrificed, tissues and blood were collected. Consequently, body weight gains, liver weights, and plasma homeostasis model of assessment-insulin resistance (HOMA-IR) values in were at higher levels in SFA and fructose groups (p < 0.05). The plasma concentrations of the non-esterified fatty acids (NEFA), triglyceride (TG), and liver steatosis were found to be at higher levels in SFA and fructose groups (p < 0.05). Moreover, the expression levels of acetyl-CoA carboxylase-1 (ACC1), insulin receptor substrate-1 (IRS1), AMP-activated protein kinase (AMPK), and toll-like receptor-4 (TLR4) in the liver were affected by the intake of SFA and fructose. Furthermore, the plasma levels of C-reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP1) and the thiobarbituric acid reactive substances (TBARS) in the liver were elevated in SFA and fructose group (p < 0.05). The plasma level of anti-inflammatory cytokine interleukin-10 (IL -10) was found to be lower in the SFA group compared to the other groups (p < 0.05). In conclusion, the inflammation and oxidation are related with the fatty acid- and fructose-induced impaired insulin signaling and fat accumulation in liver. Hence, in order to decrease the oxidative stress and pro-inflammatory response, it is substantial to reduce the saturated fat and added sugar or to replace with the unsaturated fat and complex carbohydrates in diet.