Short-term exercise reduces markers of hepatocyte apoptosis in nonalcoholic fatty liver disease

Increased hepatocyte apoptosis is a hallmark of nonalcoholic fatty liver disease (NAFLD) and contributes to the profibrogenic state responsible for the progression to nonalcoholic steatohepatitis (NASH). Strategies aimed at reducing apoptosis may result in better outcomes for individuals with NAFLD. We therefore examined the effect of a short-term exercise program on markers of apoptosis—plasma cytokeratin 18 (CK18) fragments, alanine aminotransferase (ALT), aspartate aminotransferase (AST), soluble Fas (sFas), and sFas ligand (sFasL)—in 13 obese individuals with NAFLD [body mass index 35.2 ± 1.2 kg/m2, >5% intrahepatic lipid (IHL) assessed by 1H-MR spectroscopy]. Exercise consisted of treadmill walking for 60 min/day on 7 consecutive days at ∼85% of maximal heart rate. Additionally, subjects underwent an oral glucose tolerance test and a maximal oxygen consumption (V̇o2max) test before and after the exercise intervention. The Matsuda index was used to assess insulin sensitivity. We observed significant decreases in CK18 fragments (558.4 ± 106.8 vs. 323.4 ± 72.5 U/l, P < 0.01) and ALT (30.2 ± 5.1 vs. 24.3 ± 4.8 U/l, P < 0.05), and an increase in whole body fat oxidation (49.3 ± 6.1 vs. 69.4 ± 7.1 mg/min, P < 0.05), while decreases in circulating sFasL approached statistical significance (66.5 ± 6.0 vs. 63.0 ± 5.7 pg/ml, P = 0.06), as did the relationship between percent change in circulating CK18 fragments and ALT (r = 0.55, P = 0.05). We also observed a significant correlation between changes in fat oxidation and circulating sFasL (rho = −0.65, P < 0.05). There was no change in IHL following the intervention (18.2 ± 2.5 vs. 17.5 ± 2.1%, NS). We conclude that short-term exercise reduces a circulatory marker of hepatocyte apoptosis in obese individuals with NAFLD and propose that changes in the proapoptotic environment may be mediated through improved insulin sensitivity and increased oxidative capacity.

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Relationships between Parameters of Insulin Sensitivity, Obesity and Liver Aminotransferases in Patients with Nonalcoholic Fatty Liver Disease

Hungarian Medical Journal ◽

10.1556/hmj.1.2007.4.16 ◽

2007 ◽

Vol 1 (4) ◽

pp. 537-545

Author(s):

Emil Fraenkel ◽

Ivica Lazúrová ◽

Peter Jarčuška ◽

János Fehér ◽

József Hamvas

Keyword(s):

Liver Disease ◽

Insulin Sensitivity ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Nonalcoholic Fatty Liver

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Sex Dimorphism of Nonalcoholic Fatty Liver Disease (NAFLD) in Pparg-Null Mice

International Journal of Molecular Sciences ◽

10.3390/ijms22189969 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9969

Author(s):

Mariano Schiffrin ◽

Carine Winkler ◽

Laure Quignodon ◽

Aurélien Naldi ◽

Martin Trötzmüller ◽

...

Keyword(s):

Gene Expression ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Liver Steatosis ◽

Whole Body ◽

Sex Dimorphism ◽

Nonalcoholic Fatty Liver

Men with nonalcoholic fatty liver disease (NAFLD) are more exposed to nonalcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of NALFD sex dimorphism are unclear. We combined gene expression, histological and lipidomic analyses to systematically compare male and female liver steatosis. We characterized hepatosteatosis in three independent mouse models of NAFLD, ob/ob and lipodystrophic fat-specific (PpargFΔ/Δ) and whole-body PPARγ-null (PpargΔ/Δ) mice. We identified a clear sex dimorphism occurring only in PpargΔ/Δ mice, with females showing macro- and microvesicular hepatosteatosis throughout their entire life, while males had fewer lipid droplets starting from 20 weeks. This sex dimorphism in hepatosteatosis was lost in gonadectomized PpargΔ/Δ mice. Lipidomics revealed hepatic accumulation of short and highly saturated TGs in females, while TGs were enriched in long and unsaturated hydrocarbon chains in males. Strikingly, sex-biased genes were particularly perturbed in both sexes, affecting lipid metabolism, drug metabolism, inflammatory and cellular stress response pathways. Most importantly, we found that the expression of key sex-biased genes was severely affected in all the NAFLD models we tested. Thus, hepatosteatosis strongly affects hepatic sex-biased gene expression. With NAFLD increasing in prevalence, this emphasizes the urgent need to specifically address the consequences of this deregulation in humans.

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Short-term multidisciplinary non-pharmacological intervention is effective in reducing liver fat content assessed non-invasively in patients with nonalcoholic fatty liver disease (NAFLD)

Clinics and Research in Hepatology and Gastroenterology ◽

10.1016/j.clinre.2012.10.009 ◽

2013 ◽

Vol 37 (4) ◽

pp. 353-358 ◽

Cited By ~ 21

Author(s):

Federica Scaglioni ◽

Mariano Marino ◽

Stefania Ciccia ◽

Alessia Procaccini ◽

M. Busacchi ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Fat Content ◽

Liver Fat ◽

Pharmacological Intervention ◽

Short Term ◽

Liver Fat Content ◽

Nonalcoholic Fatty Liver

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Adipose Tissue-Liver Cross Talk in the Control of Whole-Body Metabolism: Implications in Nonalcoholic Fatty Liver Disease

Gastroenterology ◽

10.1053/j.gastro.2019.12.054 ◽

2020 ◽

Vol 158 (7) ◽

pp. 1899-1912 ◽

Cited By ~ 12

Author(s):

Vian Azzu ◽

Michele Vacca ◽

Samuel Virtue ◽

Michael Allison ◽

Antonio Vidal-Puig

Keyword(s):

Adipose Tissue ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Cross Talk ◽

Fatty Liver Disease ◽

Whole Body ◽

Nonalcoholic Fatty Liver ◽

Whole Body Metabolism

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Associations among adipose tissue immunology, inflammation and exosomes and insulin sensitivity in people with obesity and nonalcoholic fatty liver disease

Gastroenterology ◽

10.1053/j.gastro.2021.05.008 ◽

2021 ◽

Author(s):

Anja Fuchs ◽

Dmitri Samovski ◽

Gordon I. Smith ◽

Vincenza Cifarelli ◽

Sarah S. Farabi ◽

...

Keyword(s):

Adipose Tissue ◽

Liver Disease ◽

Insulin Sensitivity ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Nonalcoholic Fatty Liver

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Intracellular Nicotinamide Phosphoribosyltransferase Protects against Hepatocyte Apoptosis and Is Down-Regulated in Nonalcoholic Fatty Liver Disease

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-2148 ◽

2010 ◽

Vol 95 (6) ◽

pp. 3039-3047 ◽

Cited By ~ 58

Author(s):

Tuva B. Dahl ◽

John Willy Haukeland ◽

Arne Yndestad ◽

Trine Ranheim ◽

Ivar P. Gladhaug ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Hepatocyte Apoptosis ◽

Nicotinamide Phosphoribosyltransferase ◽

Nonalcoholic Fatty Liver ◽

Related Disease ◽

Hepatic Regulation

Abstract Context: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western and non-Western countries, but its pathogenesis is not fully understood. Objective: Based on the role of nicotinamide phosphoribosyltransferase (NAMPT) in fat and glucose metabolism and cell survival, we hypothesized a role for NAMPT/visfatin in the pathogenesis of NAFLD-related disease. Design and Setting: We conducted clinical studies at a referral medical center in well-characterized NAFLD patients (n = 58) and healthy controls (n = 27). In addition we performed experimental in vitro studies in hepatocytes. Main Outcome Measures: We examined 1) the hepatic and systemic expression of NAMPT/visfatin in patients with NAFLD and control subjects, 2) the hepatic regulation of NAMPT/visfatin, and 3) the effect of NAMPT/visfatin on hepatocyte apoptosis. Results: Our main findings were as follows. 1) Patients with NAFLD had decreased NAMPT/visfatin expression both systemically in serum and within the hepatic tissue, with no difference between simple steatosis and nonalcoholic steatohepatitis. 2) By studying the hepatic regulation of NAMPT/visfatin in wild-type and peroxisome proliferators-activated receptor (PPAR)α−/− mice as well as in hepatocytes, we showed that PPARα activation and glucose may be involved in the down-regulation of hepatic NAMPT/visfatin expression in NAFLD. 4) Within the liver, NAMPT/visfatin was located to hepatocytes, and our in vitro studies showed that NAMPT/visfatin exerts antiapoptotic effects in these cells, involving enzymatic synthesis of nicotinamide adenine dinucleotide. Conclusion: Based on these findings, we suggest a role for decreased NAMPT/visfatin levels in hepatocyte apoptosis in NAFLD-related disease.

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