scholarly journals Hexanoic, Octanoic and Decanoic Acids Promote Basal and Insulin-Induced Phosphorylation of the Akt-mTOR Axis and a Balanced Lipid Metabolism in the HepG2 Hepatoma Cell Line

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2315 ◽  
Author(s):  
Sabri Rial ◽  
Gaetan Ravaut ◽  
Tommy Malaret ◽  
Karl-F. Bergeron ◽  
Catherine Mounier
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Prolonged Exposure ◽  
Hepatoma Cell ◽  
Liver Steatosis ◽  
Hepatic Insulin Resistance ◽  
Hepatoma Cell Line ◽  
Alcoholic Fatty Liver ◽  
Insulin Dependent ◽  
Chain Fatty Acids

Metabolic illnesses such as non-alcoholic fatty liver disease (NAFLD) are in constant increase worldwide. Highly consumed long chain fatty acids (LCFA) are among the most obesogenic and steatogenic nutrients. Hepatic steatosis is associated with several complications such as insulin resistance. Growing evidence points to medium chain fatty acids (MCFA), more efficiently oxidized than LCFA, as a promising dietary alternative against NAFLD. However, reports on the hepatic effects of MCFA are sometimes conflicting. In this study we exposed HepG2 cells, a human hepatocellular model, to 0.25 mM of hexanoic (C6), or octanoic (C8), and decanoic (C10) acids separately or in a C8 + C10 equimolar mix reflecting commercially available MCFA-rich oils. We found that C6, a poorly studied MCFA, as well as C8 and C10 did not provoke the deleterious lipid anabolism runaway typically induced by LCFA palmitate. MCFA tended, instead, to promote a balanced metabolic profile and were generally non-cytotoxic. Accordingly, mitochondrial integrity was mostly preserved following MCFA treatment. However, treatments with C8 induced a mitochondrial membrane potential decrease, suggesting prolonged exposure to this lipid could be problematic. Finally, MCFA treatments maintained optimal insulin sensitivity and even fostered basal and insulin-dependent phosphorylation of the Akt-mTOR pathway. Overall, MCFA could constitute an effective nutritional tool to manage liver steatosis and hepatic insulin resistance.

scholarly journals Feeding diversified protein sources exacerbates hepatic insulin resistance via increased gut microbial branched-chain fatty acids and mTORC1 signaling in obese mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Béatrice S.-Y. Choi ◽  
Noëmie Daniel ◽  
Vanessa P. Houde ◽  
Adia Ouellette ◽  
Bruno Marcotte ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Gut Microbiota ◽  
Protein Source ◽  
Hepatic Insulin Resistance ◽  
Branched Chain Fatty Acids ◽  
Mtorc1 Signaling ◽  
Branched Chain ◽  
Mixed Protein ◽  
Chain Fatty Acids

AbstractAnimal models of human diseases are classically fed purified diets that contain casein as the unique protein source. We show that provision of a mixed protein source mirroring that found in the western diet exacerbates diet-induced obesity and insulin resistance by potentiating hepatic mTORC1/S6K1 signaling as compared to casein alone. These effects involve alterations in gut microbiota as shown by fecal microbiota transplantation studies. The detrimental impact of the mixed protein source is also linked with early changes in microbial production of branched-chain fatty acids (BCFA) and elevated plasma and hepatic acylcarnitines, indicative of aberrant mitochondrial fatty acid oxidation. We further show that the BCFA, isobutyric and isovaleric acid, increase glucose production and activate mTORC1/S6K1 in hepatocytes. Our findings demonstrate that alteration of dietary protein source exerts a rapid and robust impact on gut microbiota and BCFA with significant consequences for the development of obesity and insulin resistance.

Impact of PPAR-α induction on glucose homoeostasis in alcohol-fed mice

2013 ◽  
Vol 125 (11) ◽  
pp. 501-511 ◽  
Author(s):  
Valérie Lebrun ◽  
Olivier Molendi-Coste ◽  
Nicolas Lanthier ◽  
Christine Sempoux ◽  
Patrice D. Cani ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Insulin Sensitivity ◽  
Alcohol Consumption ◽  
Insulin Signalling ◽  
Liver Steatosis ◽  
Hepatic Insulin Resistance ◽  
Alcoholic Fatty Liver ◽  
Glucose Homoeostasis

Alcohol consumption is a major cause of liver disease. It also associates with increased cardiovascular risk and Type 2 diabetes. ALD (alcoholic liver disease) and NAFLD (non-alcoholic fatty liver disease) share pathological features, pathogenic mechanisms and pattern of disease progression. In NAFLD, steatosis, lipotoxicity and liver inflammation participate to hepatic insulin resistance. The aim of the present study was to verify the effect of alcohol on hepatic insulin sensitivity and to evaluate the role of alcohol-induced steatosis and inflammation on glucose homoeostasis. C57BL/6J mice were fed for 20 days a modified Lieber–DeCarli diet in which the alcohol concentration was gradually increased up to 35% of daily caloric intake. OH (alcohol liquid diet)-fed mice had liver steatosis and inflammatory infiltration. In addition, these mice developed insulin resistance in the liver, but not in muscles, as demonstrated by euglycaemic–hyperinsulinaemic clamp and analysis of the insulin signalling cascade. Treatment with the PPAR-α (peroxisome-proliferator-activated receptor-α) agonist Wy14,643 protected against OH-induced steatosis and KC (Kupffer cell) activation and almost abolished OH-induced insulin resistance. As KC activation may modulate insulin sensitivity, we repeated the clamp studies in mice depleted in KC to decipher the role of macrophages. Depletion of KC using liposomes-encapsuled clodronate in OH-fed mice failed both to improve hepatic steatosis and to restore insulin sensitivity as assessed by clamp. Our study shows that chronic alcohol consumption induces steatosis, KC activation and hepatic insulin resistance in mice. PPAR-α agonist treatment that prevents steatosis and dampens hepatic inflammation also prevents alcohol-induced hepatic insulin resistance. However, KC depletion has little impact on OH-induced metabolic disturbances.

Therapeutic Effect of Metformin and Vitamin E Versus Prescriptive Diet in Obese Adolescents with Fatty Liver

2011 ◽  
Vol 81 (6) ◽  
pp. 398-406 ◽  
Author(s):  
Akcam ◽  
Boyaci ◽  
Pirgon ◽  
Kaya ◽  
Uysal ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Vitamin E ◽  
Fatty Liver ◽  
Liver Steatosis ◽  
Tnf Alpha ◽  
Dietary Advice ◽  
Model Assessment ◽  
Fasting Insulin ◽  
Alcoholic Fatty Liver ◽  
Obese Adolescents

Objective: The aim of the study was to determine whether metformin or vitamin E treatment for six months is effective in reducing body weight, blood pressure, and also ameliorating insulin resistance, adiponectin, and tumor necrosis factor (TNF)-alpha in obese adolescents with non-alcoholic fatty liver disease (NAFLD). Methods: Sixty-seven obese adolescents with liver steatosis (age range, 9 - 17 years) were included in the study. The metformin group received an 850-mg dose of metformin daily and the vitamin E group received 400 U vitamin E /daily, in capsule form for 6 months, plus an individually tailored diet, exercise, and behavioral therapy. Results: After 6 months later, there was a significant decline in body mass index, and fasting insulin and homeostatic model assessment (HOMA) values in all three groups. Moreover, in comparingson of changes in HOMA among the groups, the metformin- treated group showed significantly improved metabolic control and insulin sensitivity (HOMA) at the end of the study. There were no significant differences for changes of adiponectin, TNF-alpha, in all three groups after 6 months study. Conclusion: These data suggest that metformin treatment is more effective than dietary advice and vitamin E treatment in reducing insulin resistance, and also in ameliorating metabolic parameters such as fasting insulin and lipid levels, in obese adolescents having NAFLD.

scholarly journals Role of Insulin Resistance in MAFLD

2021 ◽  
Vol 22 (8) ◽  
pp. 4156
Author(s):  
Yoshitaka Sakurai ◽  
Naoto Kubota ◽  
Toshimasa Yamauchi ◽  
Takashi Kadowaki
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
De Novo Lipogenesis ◽  
Hepatic Insulin Resistance ◽  
Metabolic Dysfunction ◽  
Alcoholic Fatty Liver ◽  
Fat Accumulation

Many studies have reported that metabolic dysfunction is closely involved in the complex mechanism underlying the development of non-alcoholic fatty liver disease (NAFLD), which has prompted a movement to consider renaming NAFLD as metabolic dysfunction-associated fatty liver disease (MAFLD). Metabolic dysfunction in this context encompasses obesity, type 2 diabetes mellitus, hypertension, dyslipidemia, and metabolic syndrome, with insulin resistance as the common underlying pathophysiology. Imbalance between energy intake and expenditure results in insulin resistance in various tissues and alteration of the gut microbiota, resulting in fat accumulation in the liver. The role of genetics has also been revealed in hepatic fat accumulation and fibrosis. In the process of fat accumulation in the liver, intracellular damage as well as hepatic insulin resistance further potentiates inflammation, fibrosis, and carcinogenesis. Increased lipogenic substrate supply from other tissues, hepatic zonation of Irs1, and other factors, including ER stress, play crucial roles in increased hepatic de novo lipogenesis in MAFLD with hepatic insulin resistance. Herein, we provide an overview of the factors contributing to and the role of systemic and local insulin resistance in the development and progression of MAFLD.

scholarly journals Beneficial effect of omarigliptin on diabetic patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Sachiko Hattori ◽  
Kazuomi Nomoto ◽  
Tomohiko Suzuki ◽  
Seishu Hayashi
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Liver Function ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Hepatic Insulin Resistance ◽  
Diabetic Patients ◽  
Alcoholic Fatty Liver ◽  
Dpp4 Inhibitor ◽  
Alcoholic Fatty Liver Disease

Abstract Background Dipeptidyl peptidase 4 (DPP4) is a serine exopeptidase able to inactivate various oligopeptides, and also a hepatokine. Hepatocyte-specific overexpression of DPP4 is associated with hepatic insulin resistance and liver steatosis. Method We examined whether weekly DPP4 inhibitor omarigliptin (OMG) can improve liver function as well as levels of inflammation and insulin resistance in type 2 diabetic patients with non-alcoholic fatty liver disease (NAFLD). Further, we investigated the effects of OMG in a diabetic patient with biopsy-confirmed nonalcoholic steatohepatitis (NASH). Results In NAFLD patients, OMG significantly decreased levels of aminotransferase, aspartate aminotransferase, gamma-glutamyl transpeptidase, homeostatic model assessment of insulin resistance (HOMA-IR), and high-sensitivity C-reactive protein (hsCRP), while no significant change was seen in hemoglobin A1c or body mass index. In the NASH patient, liver function improved markedly, and levels of the hepatic fibrosis marker FIB-4 decreased in parallel with HOMA-IR and hsCRP. Slight but clear improvements in intrahepatic fat deposition and fibrosis appeared to be seen on diagnostic ultrasonography. Conclusion Weekly administration of the DPP4 inhibitor OMG in ameliorating hepatic insulin resistance may cause beneficial effects in liver with NAFLD/NASH.

scholarly journals Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease

2020 ◽  
Author(s):  
Kasper W. ter Horst ◽  
Daniel F. Vatner ◽  
Dongyan Zhang ◽  
Gary W. Cline ◽  
Mariette T. Ackermans ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Bariatric Surgery ◽  
Liver Disease ◽  
Fatty Liver ◽  
Insulin Signaling ◽  
Fatty Liver Disease ◽  
De Novo ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Alcoholic Fatty Liver

<b>Objective</b>: Both glucose and triglyceride production are increased in Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). For decades, the leading hypothesis to explain these paradoxical observations has been selective hepatic insulin resistance, wherein insulin drives <i>de novo</i> lipogenesis (DNL), while failing to suppress glucose production. Here, we aimed to test this hypothesis in humans. <p><b>Research Design and Methods</b>: We recruited obese subjects who met criteria for bariatric surgery with (n=16) or without (n=15) NAFLD and assessed: i) insulin-mediated regulation of hepatic and peripheral glucose metabolism using hyperinsulinemic-euglycemic clamps with [6,6-<sup>2</sup>H<sub>2</sub>]glucose, ii) fasting and carbohydrate-driven hepatic DNL using deuterated water (<sup>2</sup>H<sub>2</sub>O), and iii) hepatocellular insulin signaling in liver biopsies collected during bariatric surgery.</p> <p><b>Results</b>: As compared with subjects without NAFLD, subjects with NAFLD demonstrated impaired insulin-mediated suppression of glucose production and attenuated -not increased- glucose-stimulated/high-insulin lipogenesis. Fructose-stimulated/low-insulin lipogenesis was intact. Hepatocellular insulin signaling, assessed for the first time in humans, exhibited a proximal block in insulin-resistant subjects: signaling was attenuated from the level of the insulin receptor through both glucose <i>and</i> lipogenesis pathways. The carbohydrate-regulated lipogenic transcription factor <i>ChREBP</i> was increased in subjects with NAFLD. </p> <b>Conclusions</b>: Acute increases in lipogenesis in humans with NAFLD are not explained by altered molecular regulation of lipogenesis through a paradoxical increase in lipogenic insulin action; rather, increases in lipogenic substrate availability may be the key. <a></a>

scholarly journals Short-chain fatty acids and inulin, but not guar gum, prevent diet-induced obesity and insulin resistance through differential mechanisms in mice

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Karolin Weitkunat ◽  
Christin Stuhlmann ◽  
Anna Postel ◽  
Sandra Rumberger ◽  
Maria Fankhänel ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Guar Gum ◽  
Short Chain Fatty Acids ◽  
Short Chain ◽  
Diet Induced Obesity ◽  
Chain Fatty Acids

scholarly journals The Protective Effect of Cynara Cardunculus Extract in Diet-Induced NAFLD: Involvement of OCTN1 and OCTN2 Transporter Subfamily

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1435
Author(s):  
Francesca Oppedisano ◽  
Carolina Muscoli ◽  
Vincenzo Musolino ◽  
Cristina Carresi ◽  
Roberta Macrì ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protective Effect ◽  
Liver Steatosis ◽  
Serum Glucose ◽  
Cynara Cardunculus ◽  
Alcoholic Fatty Liver ◽  
Oral Supplementation ◽  
Increased Risk ◽  
Enhanced Expression ◽  
Alcoholic Fatty Liver Disease

Hyperlipidemia and insulin-resistance are often associated with Non-Alcoholic Fatty Liver Disease (NAFLD) thereby representing a true issue worldwide due to increased risk of developing cardiovascular and systemic disorders. Although clear evidence suggests that circulating fatty acids contribute to pathophysiological mechanisms underlying NAFLD and hyperlipidemia, further studies are required to better identify potential beneficial approaches for counteracting such a disease. Recently, several artichoke extracts have been used for both reducing hyperlipidemia, insulin-resistance and NAFLD, though the mechanism is unclear. Here we used a wild type of Cynara Cardunculus extract (CyC), rich in sesquiterpens and antioxidant active ingredients, in rats fed a High Fat Diet (HFD) compared to a Normal Fat Diet (NFD). In particular, in rats fed HFD for four consecutive weeks, we found a significant increase of serum cholesterol, triglyceride and serum glucose. This effect was accompanied by increased body weight and by histopathological features of liver steatosis. The alterations of metabolic parameters found in HFDs were antagonised dose-dependently by daily oral supplementation of rats with CyC 10 and 20 mg/kg over four weeks, an effect associated to significant improvement of liver steatosis. The effect of CyC (20 mg/kg) was also associated to enhanced expression of both OCTN1 and OCTN2 carnitine-linked transporters. Thus, present data suggest a contribution of carnitine system in the protective effect of CyC in diet-induced hyperlipidemia, insulin-resistance and NAFLD.

scholarly journals Article Commentary: A Role for IR-β in the Free Fatty Acid Mediated Development of Hepatic Insulin Resistance?

2009 ◽  
Vol 2 ◽  
pp. BCI.S2996
Author(s):  
Samit Shah ◽  
Arthur G. Cox
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Free Fatty Acids ◽  
Pi3k Pathway ◽  
Hepatic Insulin Resistance ◽  
Hamster Model ◽  
High Concentrations ◽  
Nfκb Pathway

Several studies have been conducted to elucidate the role of free fatty acids (FFAs) in the pathogenesis of type 2 diabetes, but the exact molecular mechanism by which FFAs alter glucose metabolism in the liver is still not completely understood. 1 – 4 In a recent publication, Ragheb and coworkers have examined the effect of free fatty acid (FFA) treatment on insulin signaling and insulin resistance by using immunoprecipitation and immunoblotting to study the effect of high concentrations of insulin and FFAs on insulin receptor-beta (IR-β) and downstream elements in the PI3K pathway using the fructose-fed hamster model. 5 Their results clearly show that free fatty acids have an insignificant effect on IR-β and supports previous findings that FFAs lead to insulin resistance in the liver via the PKC-NFκB pathway. 2 , 3

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