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.

scholarly journals NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)

2016 ◽  
Vol 23 (01) ◽  
pp. 029-033
Author(s):  
Nusrat Alavi ◽  
Saima Amin ◽  
Madiha Mumtaz
Keyword(s):  
Fatty Liver ◽  
Laboratory Data ◽  
Diabetic Group ◽  
Radiology Department ◽  
P Value ◽  
Diabetic Patients ◽  
Type Ii ◽  
Type 2 Diabetic Patients ◽  
Cross Sectional ◽  
Alcoholic Fatty Liver

Objectives: To assess the incidence of NAFLD and biochemical profile in nondiabeticand diabetic patients. Study Design: It was a cross sectional descriptive study. Setting:Shalamar Institute of Health Sciences (SIHS), Lahore. Period: Six months, Jan 2015 to Jun2015. Methods: The patients coming to the Radiology Department for abdominal ultrasoundwere age and sex matched into fatty liver and non-fatty liver groups and diabetic and nondiabeticgroups and were further evaluated on the basis of glucose, alanine aminotransferase(ALT) and triglycerides (TG) levels from the laboratory data. Results: The findings of allbiochemical parameters were raised in diabetic patients with fatty liver as well as in non-fattyliver diabetic group and the differences were found to be statistically (P value less than 0.05)significant. In non-diabetic group, out of 200 subjects 56.5% had NAFLD whereas 43.5% hadno NAFLD. In diabetic patients, out of 200 patients 69% had NAFLD and 31% had no NAFLDand the difference was significant statistically (P= <0.05). The prevalence of NAFLD 12.5%was higher in type-2 diabetic patients as compared to non-diabetic group. In non-diabeticgroup, 113 subjects had TG value of 181±82.49, while 87 subjects had TG of 141±44.5. Indiabetic patients, 138 patients had TG value of 467±277.64 whereas 62 patients had TG valueof 178±46.52, which was statistically significant (P= <0.05). Conclusion: Fatty liver is animportant marker for metabolic syndrome which is a pre-diabetic condition. The occurrenceof NAFLD was elevated in type II patients of diabetes. The traditional risk factors for NAFLDare considered to be female sex, type II diabetes mellitus, obesity and hypertriglyceridemia.Hyperglycemia, hypertriglyceridemia and elevated ALT were observed more repeatedly in fattyliver than in non-fatty liver (type II) diabetic patients

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.

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