Dissociation of hepatic insulin resistance from susceptibility of nonalcoholic fatty liver disease induced by a high-fat and high-carbohydrate diet in mice
Liver steatosis in nonalcoholic fatty liver disease is affected by genetics, diet, and associated with insulin resistance (IR) in hepatic and peripheral tissues. Here, we aimed to characterize the severity of diet-induced steatosis, obesity, and IR in two phylogenetically distant mouse strains, C57BL/6J and DBA/2J. To this end, mice (male, 8 weeks) were fed a high fat and high carbohydrate (HFHC) or control diet for 16 weeks followed by applying a combination of classic physiological, biochemical and pathological studies to determine obesity and hepatic steatosis. Peripheral IR was characterized by measuring blood glucose level, serum insulin level, HOMA-IR, glucose intolerance, insulin intolerance, and AKT phosphorylation in adipose tissues, whereas the level of hepatic IR was determined by measuring insulin-triggered hepatic AKT phosphorylation. We discovered that both C57BL/6J and DBA/2J mice developed obesity to a similar degree without feature of liver inflammation after feeding HFHC-diet for 16 weeks. C57BL/6J mice in the HFHC-diet group exhibited severe pan-lobular steatosis, a marked increase in hepatic triglyceride levels, and profound peripheral IR. In contrast, DBA/2J mice in the HFHC-diet group developed only a mild degree of pericentrilobular hepatic steatosis that was associated with moderate changes in peripheral IR. Interestingly, both C57BL/6J and DBA/2J developed severe hepatic IR after HFHC-diet treatment. Collectively, these data suggest the severity of diet-induced hepatic steatosis is correlated to the level of peripheral IR, not with the severity of obesity and hepatic insulin resistance. Peripheral rather than hepatic IR is a dominant factor of pathophysiology in nonalcoholic fatty liver disease.
Available from: Mariola Olkowicz
- "The major problem is the excess of carbohydrates in the diet, especially of simple sugars and those which in the process of digestion are easy to transform; and triacylglycerols , which have the highest energy density (9 kcal/g). As a consequence, there is an abnormal accumulation of body fat  . "
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ABSTRACT: The aim of this study was to investigate the effect of black chokeberry (Aronia melanocarpa L.) extract on the activity of porcine pancreatic α-amylase and lipase. An in vitro study demonstrated that three kinds of chokeberry extracts: methanolic, water and acetic caused inhibition of α-amylase and lipase. The methanolic and acetic extracts exhibited the highest inhibitory activities against α-amylase with the IC50 values of 10.31 ± 0.04 mg/ml and pancreatic lipase 83.45 ± 0.50 mg/ml, respectively. In order to identify the compounds which may be the potential inhibitors of α-amylase and lipase, chokeberry extract was analysed by preparative reverse phase chromatography and high performance liquid chromatography-mass spectrometry (HPLC-MS). These studies have shown that both anthocyanins and phenolic acids are compounds which inhibit the ability of the reaction catalysed by α-amylase and lipase. The most effective inhibitor of pancreatic α-amylase was chlorogenic acid (IC50 = 0.57 ± 0.16 mg/ml). In the group of anthocyanins the most potent inhibitor of α-amylase was cyanidin-3-glucoside (IC50 = 1.74 ± 0.04 mg/ml), which also showed an ability to inhibit the reaction catalysed by pancreatic lipase (IC50 = 1.17 ± 0.05 mg/ml). These findings seem to indicate the use of chokeberry as a functional food component, contributing to its anti-obesity activities.
PROCESS BIOCHEMISTRY 09/2014; 49(9). DOI:10.1016/j.procbio.2014.06.002 · 2.52 Impact Factor
Available from: Rachel J Perry
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ABSTRACT: Non-alcoholic fatty liver disease and its downstream sequelae, hepatic insulin resistance and type 2 diabetes, are rapidly growing epidemics, which lead to increased morbidity and mortality rates, and soaring health-care costs. Developing interventions requires a comprehensive understanding of the mechanisms by which excess hepatic lipid develops and causes hepatic insulin resistance and type 2 diabetes. Proposed mechanisms implicate various lipid species, inflammatory signalling and other cellular modifications. Studies in mice and humans have elucidated a key role for hepatic diacylglycerol activation of protein kinase Cε in triggering hepatic insulin resistance. Therapeutic approaches based on this mechanism could alleviate the related epidemics of non-alcoholic fatty liver disease and type 2 diabetes.
Nature 06/2014; 510(7503):84-91. DOI:10.1038/nature13478 · 41.46 Impact Factor
Available from: Mariana Machado
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ABSTRACT: Non-alcoholic steatohepatitis (NASH), the potentially progressive form of nonalcoholic fatty liver disease (NAFLD), is the pandemic liver disease of our time. Although there are several animal models of NASH, consensus regarding the optimal model is lacking. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD) diet and Western diet.
Mice were fed standard chow, MCD diet for 8 weeks, or Western diet (45% energy from fat, predominantly saturated fat, with 0.2% cholesterol, plus drinking water supplemented with fructose and glucose) for 16 weeks. Liver pathology and metabolic profile were compared.
The metabolic profile associated with human NASH was better mimicked by Western diet. Although hepatic steatosis (i.e., triglyceride accumulation) was also more severe, liver non-esterified fatty acid content was lower than in the MCD diet group. NASH was also less severe and less reproducible in the Western diet model, as evidenced by less liver cell death/apoptosis, inflammation, ductular reaction, and fibrosis. Various mechanisms implicated in human NASH pathogenesis/progression were also less robust in the Western diet model, including oxidative stress, ER stress, autophagy deregulation, and hedgehog pathway activation.
Feeding mice a Western diet models metabolic perturbations that are common in humans with mild NASH, whereas administration of a MCD diet better models the pathobiological mechanisms that cause human NAFLD to progress to advanced NASH.
PLoS ONE 05/2015; 10(5):e0127991. DOI:10.1371/journal.pone.0127991 · 3.23 Impact Factor
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