scholarly journals Defective FXR-SHP Regulation in Obesity Aberrantly Increases miR-802 Expression, Promoting Insulin Resistance and Fatty Liver

2021 ◽  
Author(s):  
Sunmi Seok ◽  
Hao Sun ◽  
Young-Chae Kim ◽  
Byron Kemper ◽  
Jongsook Kim Kemper
Keyword(s):  
Insulin Resistance ◽  
Fatty Liver ◽  
Farnesoid X Receptor ◽  
Dependent Manner ◽  
Obese Mice ◽  
Metabolic Complications ◽  
Alcoholic Fatty Liver ◽  
Beneficial Effects ◽  
Elevated Expression ◽  
Glucose And Lipid Homeostasis

Aberrantly elevated expression in obesity of microRNAs (miRs), including miR-802, contributes to obesity-associated metabolic complications but the mechanisms underlying the elevated expression are unclear. Farnesoid-X-Receptor (FXR), a key regulator of hepatic energy metabolism, has great potential for treatment of obesity-related diseases. We examined whether a nuclear receptor cascade involving FXR and FXR-induced Small Heterodimer Partner (SHP) regulates expression of <i>miR-802</i> to maintain glucose and lipid homeostasis. Hepatic miR-802 levels are increased in FXR-knockout (KO) or SHP-KO mice and are decreased by activation of FXR in a SHP-dependent manner. Mechanistically, transactivation of <i>miR-802 </i>by<i> </i>Aromatic Hydrocarbon Receptor (AHR) is inhibited by SHP. In obese mice, activation of FXR by obeticholic acid treatment reduced miR-802 levels and improved insulin resistance and hepatosteatosis, but these beneficial effects were largely abolished by overexpression of miR-802. In non-alcoholic fatty liver disease patients and obese mice, occupancy of SHP is reduced and that of AHR is modestly increased at the <i>miR-802</i> promoter, consistent with elevated hepatic miR-802 expression. These results demonstrate that normal inhibition of <i>miR-802</i> by FXR-SHP is defective in obesity, resulting in increased <i>miR-802</i> levels, insulin resistance and fatty liver. This FXR-SHP-miR-802 pathway may present novel targets for treating type 2 diabetes and NAFLD.

scholarly journals Defective FXR-SHP Regulation in Obesity Aberrantly Increases miR-802 Expression, Promoting Insulin Resistance and Fatty Liver

2021 ◽  
Author(s):  
Sunmi Seok ◽  
Hao Sun ◽  
Young-Chae Kim ◽  
Byron Kemper ◽  
Jongsook Kim Kemper
Keyword(s):  
Insulin Resistance ◽  
Fatty Liver ◽  
Farnesoid X Receptor ◽  
Dependent Manner ◽  
Obese Mice ◽  
Metabolic Complications ◽  
Alcoholic Fatty Liver ◽  
Beneficial Effects ◽  
Elevated Expression ◽  
Glucose And Lipid Homeostasis

Aberrantly elevated expression in obesity of microRNAs (miRs), including miR-802, contributes to obesity-associated metabolic complications but the mechanisms underlying the elevated expression are unclear. Farnesoid-X-Receptor (FXR), a key regulator of hepatic energy metabolism, has great potential for treatment of obesity-related diseases. We examined whether a nuclear receptor cascade involving FXR and FXR-induced Small Heterodimer Partner (SHP) regulates expression of <i>miR-802</i> to maintain glucose and lipid homeostasis. Hepatic miR-802 levels are increased in FXR-knockout (KO) or SHP-KO mice and are decreased by activation of FXR in a SHP-dependent manner. Mechanistically, transactivation of <i>miR-802 </i>by<i> </i>Aromatic Hydrocarbon Receptor (AHR) is inhibited by SHP. In obese mice, activation of FXR by obeticholic acid treatment reduced miR-802 levels and improved insulin resistance and hepatosteatosis, but these beneficial effects were largely abolished by overexpression of miR-802. In non-alcoholic fatty liver disease patients and obese mice, occupancy of SHP is reduced and that of AHR is modestly increased at the <i>miR-802</i> promoter, consistent with elevated hepatic miR-802 expression. These results demonstrate that normal inhibition of <i>miR-802</i> by FXR-SHP is defective in obesity, resulting in increased <i>miR-802</i> levels, insulin resistance and fatty liver. This FXR-SHP-miR-802 pathway may present novel targets for treating type 2 diabetes and NAFLD.

Non-Alcoholic Steatohepatitis: From Pathophysiology to Novel Therapies

2016 ◽  
Vol 34 (4) ◽  
pp. 356-363 ◽  
Author(s):  
Daniel Jahn ◽  
Monika Rau ◽  
Julia Wohlfahrt ◽  
Heike M. Hermanns ◽  
Andreas Geier
Keyword(s):  
Fatty Liver ◽  
Farnesoid X Receptor ◽  
Liver Fat ◽  
Metabolic Effects ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Double Blind ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Elevated Expression

Non-alcoholic fatty liver (NAFL) disease is defined by an accumulation of liver fat exceeding 5% of its weight in the absence of significant alcoholic intake. In 5-20%, there is a progression from NAFL to non-alcoholic steatohepatitis (NASH). Until now, it is not well understood why only some patients develop NASH, and currently, no drugs are licensed for this indication. Different T-cell populations such as T-regulatory, Th1 and Th17 cells play a central role in the immunopathogenesis of fatty liver disease and open the option of future interleukin (IL)-17-based therapeutics. The inflammatory process underlying NASH is furthermore characterized by elevated expression of pro-inflammatory cytokines such as TNFα and IL-1β. Anakinra, a recombinant version of IL-1Ra shows promising metabolic effects with improved hyperglycemia and beta-cell secretory function in a double-blind placebo controlled randomized trial in type 2 diabetic patients but such studies are still in their preliminary stages for NASH. Several studies point out that bile acid farnesoid X receptor (FXR)-mediated signals (such as the enterohepatic hormone fibroblast growth factor 15/19) are involved in the regulation of triglyceride and glucose metabolism. Recent clinical trials have revealed a beneficial impact of the FXR agonist obeticholic acid on body weight, insulin sensitivity and liver histology in patients with NASH. Further potential novel therapeutic targets in NASH are currently in phase II clinical development.

Abstract 398: Bile Acid Receptor Activation Ameliorates Metabolic Disorders by Differentially Activating FXR or TGR5

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Kavita S Jadhav ◽  
Yang Xu ◽  
Yanqiao Zhang
Keyword(s):  
Bile Acid ◽  
Metabolic Regulation ◽  
Metabolic Disorders ◽  
Receptor Activation ◽  
Farnesoid X Receptor ◽  
Dependent Manner ◽  
Alcoholic Fatty Liver ◽  
Beneficial Effects ◽  
Dual Activation ◽  
Pparγ Expression

Objectives: Activation of the bile acid (BA) receptors farnesoid X receptor (FXR) or TGR5 has beneficial effects on metabolic homeostasis. However, activation of FXR may increase obesity and activation of TGR5 has little effect on lipid metabolism. As such, dual activation of FXR and TGR5 appears to be a more attractive approach for treatment of common metabolic disorders. So far, the role of BA receptor activation in metabolic regulation is not well characterized. Methods: We utilized wild-type (WT) mice, Tgr5 -/- mice, Fxr -/- mice, Apoe -/- mice and Shp -/- mice to investigate whether and how BA receptor activation by INT-767, a semisynthetic agonist for both FXR and TGR5, can prevent or reverse diet-induced metabolic disorders. Results: INT-767 reversed HFD-induced obesity and hyperglycemia in a TGR5-dependent manner and inhibited the development of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Mechanistically, INT-767 improved lipid homeostasis by activation of FXR and increased energy expenditure. Furthermore, activation of FXR inhibited several lipogeneic genes in the liver. We identified peroxisome proliferation-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (CEBPα) as novel downstream targets of FXR. FXR inhibited PPARγ expression by inducing SHP (small heterodimer partner) whereas the inhibition of CEBPα by FXR is SHP-independent. Conclusions: BA receptor activation can prevent and reverse obesity, NAFLD and atherosclerosis by specific activation of FXR or TGR5. Our data suggest that compared of activation of FXR or TGR5 alone, dual activation of both FXR and TGR5 is a more attractive strategy for treatment of common metabolic disorders. Key words: FXR; TGR5; Atherosclerosis; Obesity; NAFLD; Lipogenesis

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.

Non-Alcoholic Fatty Liver Disease in Overweight Children and its Relationship with Retinol Serum Levels

2008 ◽  
Vol 78 (1) ◽  
pp. 27-32 ◽  
Author(s):  
Suano de Souza ◽  
Silverio Amancio ◽  
Saccardo Sarni ◽  
Sacchi Pitta ◽  
Fernandes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Lipid Profile ◽  
Fatty Liver Disease ◽  
Thiobarbituric Acid ◽  
Serum Levels ◽  
Control Group ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

Objectives: To evaluate the frequency of non-alcoholic fatty liver disease, the retinol serum levels, lipid profile, and insulin resistance in overweight/obese children. To relate these biochemical variables with the risk of this disease in the population studied. Methods: The study was cross-sectional and prospective, with 46 overweight/obese school children (28 female, 18 male; mean age 8.6 years). The control group consisted of 45 children, paired by age and gender. Hepatic steatosis, evaluated by ultrasound, was classified as normal, mild, moderate, or severe. Also evaluated were serum retinol levels; thiobarbituric acid reactive substances; lipid profile; and fasting glucose and serum insulin levels, used for the calculation of the Homeostasis Model Assessment. Results: Hepatic ultrasound alterations were found in 56.5% and 48,9% of the overweight/obese and control group children, respectively. Presence of obesity was associated with high levels of triglycerides (OR = 4.6; P = 0.002). In the studied children, the risk of steatosis was related to a trend to a higher percentage of retinol inadequacy (OR = 2.8; p = 0.051); there was no association with thiobarbituric acid reactive substances, lipid profile, or insulin resistance. Conclusions: The high frequency of non-alcoholic fatty liver disease in both groups, evaluated by hepatic ultrasound, in low-socioeconomic level children, independent of nutritional condition and without significant association with insulin resistance, emphasizes that especially in developing countries, other risk factors such as micronutrient deficiencies (e.g. vitamin A) are involved.

Non-alcoholic fatty liver disease and its association with insulin resistance in an obese population

2018 ◽  
Author(s):  
Frederique Van de Velde ◽  
Marlies Bekaert ◽  
Anne Hoorens ◽  
Marleen Praet ◽  
Arsene-Helene Batens ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Obese Population ◽  
Alcoholic Fatty Liver Disease

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.

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