Peroxisomal β-oxidation regulates whole body metabolism, inflammatory vigor, and pathogenesis of nonalcoholic fatty liver disease

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 exercise reduces markers of hepatocyte apoptosis in nonalcoholic fatty liver disease

Journal of Applied Physiology ◽

10.1152/japplphysiol.00127.2012 ◽

2012 ◽

Vol 113 (1) ◽

pp. 1-6 ◽

Cited By ~ 50

Author(s):

Ciaran E. Fealy ◽

Jacob M. Haus ◽

Thomas P. J. Solomon ◽

Mangesh Pagadala ◽

Chris A. Flask ◽

...

Keyword(s):

Liver Disease ◽

Insulin Sensitivity ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Fat Oxidation ◽

Whole Body ◽

Hepatocyte Apoptosis ◽

Short Term ◽

Nonalcoholic Fatty Liver

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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Whole‐body vibration for patients with nonalcoholic fatty liver disease: a 6‐month prospective study

Physiological Reports ◽

10.14814/phy2.14062 ◽

2019 ◽

Vol 7 (9) ◽

pp. e14062

Author(s):

Sechang Oh ◽

Natsumi Oshida ◽

Noriko Someya ◽

Tsuyoshi Maruyama ◽

Tomonori Isobe ◽

...

Keyword(s):

Liver Disease ◽

Prospective Study ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Whole Body Vibration ◽

Whole Body ◽

Nonalcoholic Fatty Liver ◽

Body Vibration

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GP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity

Nature Communications ◽

10.1038/s41467-021-27309-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yumeng Peng ◽

Qiang Zeng ◽

Luming Wan ◽

Enhao Ma ◽

Huilong Li ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Whole Body ◽

Specific Gene ◽

Rab Gtpase ◽

Gtpase Activating Protein ◽

Alcoholic Fatty Liver ◽

Nonalcoholic Fatty Liver ◽

Whole Body Metabolism

AbstractThe prevalence of non-obese nonalcoholic fatty liver disease (NAFLD) is increasing worldwide with unclear etiology and pathogenesis. Here, we show GP73, a Golgi protein upregulated in livers from patients with a variety of liver diseases, exhibits Rab GTPase-activating protein (GAP) activity regulating ApoB export. Upon regular-diet feeding, liver-GP73-high mice display non-obese NAFLD phenotype, characterized by reduced body weight, intrahepatic lipid accumulation, and gradual insulin resistance development, none of which can be recapitulated in liver-GAP inactive GP73-high mice. Common and specific gene expression signatures associated with GP73-induced non-obese NAFLD and high-fat diet (HFD)-induced obese NAFLD are revealed. Notably, metformin inactivates the GAP activity of GP73 and alleviates GP73-induced non-obese NAFLD. GP73 is pathologically elevated in NAFLD individuals without obesity, and GP73 blockade improves whole-body metabolism in non-obese NAFLD mouse model. These findings reveal a pathophysiological role of GP73 in triggering non-obese NAFLD and may offer an opportunity for clinical intervention.

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Associations between Phase Angle Values Obtained by Bioelectrical Impedance Analysis and Nonalcoholic Fatty Liver Disease in an Overweight Population

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2020/8888405 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7

Author(s):

Guangya Chen ◽

Yi Lv ◽

Wei Ni ◽

Qingxin Shi ◽

Xingliang Xiang ◽

...

Keyword(s):

Logistic Regression ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Impedance Analysis ◽

Whole Body ◽

Regression Analyses ◽

Nonalcoholic Fatty Liver ◽

The Right

Objective. There is a limited diagnosis of nonalcoholic fatty liver disease (NAFLD). Thus, the noninvasive assessments are worth exploring. We determined the associations of phase angles (PhAs) obtained from bioelectric impedance analysis (BIA) with the risk of NAFLD in an overweight population. Methods. A study involving 953 overweight participants was conducted in Wuhan city, China. The associations between PhAs (right arm, left arm, body trunk, right leg, left leg, and whole body) and the risk of NAFLD were conducted using multivariate logistic regression analyses. The associations of PhAs with the controlled attenuation parameter (CAP), a noninvasive assessment of liver steatosis and fibrosis, were also evaluated by both linear and logistic regression analyses. Results. The PhA values of the whole body, trunk, and legs were significantly lower (P<0.05) in the NAFLD group than the non-NAFLD group. After adjustment for BMI, gender, education, income/year, hyperlipidemia, hypertension, diabetes, smoking, passive smoking, and drinking, significant associations of PhA values of the right leg, left leg, and whole body with the risk of NAFLD were observed. In addition, the PhA of the right leg, left leg, and whole body were significantly related to the CAP values. Further stratified analyses indicated that these associations were significant in the participants with BMI <30, but not in the participants with BMI ≥30. Conclusions. PhAs might be effective indicators in the management of NAFLD among overweight people.

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