Nonalcoholic fatty liver disease: Updates on associations with the metabolic syndrome and lipid profile and effects of treatment with PPAR-γ agonists

Polyzos, Stergios A.; Bugianesi, Elisabetta; Mantzoros, Christos S.

doi:10.1016/j.metabol.2016.08.001

Cited by 19 publications

(12 citation statements)

References 44 publications

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“…Nonalcoholic fatty liver disease (NAFLD), a chronic liver disease affecting 30% of the general population and 40% to 70% of obese individuals [ 1 2 ], is considered the hepatic manifestation of metabolic syndrome [ 3 4 5 6 ] and its prevalence increases continuously and concurrently with obesity and type 2 diabetes mellitus (T2DM) [ 7 8 9 10 ]. NAFLD is defined as the accumulation of excessive fat in the liver of patients without history of alcohol abuse or other causes of hepatic steatosis.…”

Section: Introductionmentioning

confidence: 99%

Association of Adipokines with Development and Progression of Nonalcoholic Fatty Liver Disease

2018

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Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting 30% of the general population and 40% to 70% of obese individuals. Adipose tissue plays a crucial role in its pathogenesis, as it produces and secretes pro- and anti-inflammatory cytokines called adipokines. Adiponectin and leptin have well-determined actions in terms of NAFLD pathophysiology. Adiponectin deficiency is associated with a pro-inflammatory condition, as it is observed in obesity and other metabolic disorders. On the other hand, increased leptin levels, above the normal levels, act as a pro-inflammatory stimulus. Regarding other adipokines (resistin, visfatin, chemerin, retinol-binding protein 4, irisin), data about their contribution to NAFLD pathogenesis and progression are inconclusive. In addition, pharmacological agents like thiazolidinediones (pioglitazone and rosiglitazone), that are used in the management of NAFLD exert favourable effects on adipokine levels, which in turn may contribute to the improvement of liver function. This review summarizes the current knowledge and developments in the association between adipokines and NAFLD and discusses possible therapeutic implications targeting the modulation of adipokine levels as a potential tool for the treatment of NAFLD.

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Section: Introductionmentioning

confidence: 99%

Association of Adipokines with Development and Progression of Nonalcoholic Fatty Liver Disease

2018

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“…The identified PPARs differ from each other in terms of tissue distribution and ligand specificity, acting as important regulators of many genes involved in adipogenesis, glucose homeostasis, lipid metabolism, and inflammation . Given the therapeutic potential for type 2 diabetes, PPARγ attracted extensive clinical interest and therefore has been extensively studied and tested in clinics for the treatment of NAFLD patients . However, the results from the treatment of NAFLD by PPARγ agonists have been mixed, which is partly due to the complex cell‐specific and tissue‐specific PPARγ functions.…”

mentioning

confidence: 99%

“…(15) Given the therapeutic potential for type 2 diabetes, PPARc attracted extensive clinical interest and therefore has been extensively studied (16) and tested in clinics for the treatment of NAFLD patients. (17)(18)(19) However, the results from the treatment of NAFLD by PPARc agonists have been mixed, (20)(21)(22) which is partly due to the complex cell-specific and tissue-specific PPARc functions. PPARc is highly expressed in adipose tissues but at very low levels in normal liver.…”

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confidence: 99%

Inflammation is independent of steatosis in a murine model of steatohepatitis

Wang

Cai

et al. 2017

Hepatology

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Obesity and alcohol consumption synergistically promote steatohepatitis, and neutrophil infiltration is believed to be associated with steatosis. However, the underlying mechanisms remain obscure. Peroxisome proliferator-activated receptor-gamma (PPARγ) plays a complex role in lipid metabolism and inflammation, therefore, the purpose of this study was to dissect its role in regulating steatosis and neutrophil infiltration in a clinically relevant mouse steatohepatitis model of 3-month high-fat diet (HFD) feeding plus a binge of ethanol (HFD - plus-binge ethanol). Hepatocyte-specific Pparg disruption reduced liver steatosis, but surprisingly increased hepatic neutrophil infiltration after HFD-plus-binge ethanol. Knockout or knockdown of the PPARγ target gene, fat-specific protein 27 (Fsp27), reduced steatosis without affecting neutrophil infiltration in this model. Moreover, hepatocyte-specific deletion of the Pparg gene but not the Fsp27 gene markedly upregulated hepatic levels of Cxcl1 (a chemokine for neutrophil infiltration) in HFD-plus-binge ethanol-fed mice. In vitro, deletion of the Pparg gene also highly augmented palmitic acid or TNF-α induction of Cxcl1 in mouse hepatocytes. In contrast, activation of PPARγ with a PPARγ agonist attenuated Cxcl1 expression in hepatocytes. Palmitic acid also upregulated IL-8 (a key chemokine for human neutrophil recruitment) expression in human hepatocytes, which was attenuated and enhanced by co-treatment with a PPARγ agonist and antagonist, respectively. Finally, acute ethanol binge markedly attenuated HFD-induced hepatic PPARγ activation, which contributed to the upregulation of hepatic Cxcl1 expression post HFD-plus-bigne ethanol. In conclusion, hepatic PPARγ plays an opposing role in controlling steatosis and neutrophil infiltration, leading to dissociation between steatosis and inflammation. Acute ethanol gavage attenuates hepatic PPARγ activation and subsequently upregulates hepatic CXCL1/IL-8 expression, thereby exacerbating hepatic neutrophil infiltration.

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“…This supplement to "Metabolism, Clinical and Experimental" is dedicated to nonalcoholic fatty liver disease (NAFLD), a disease closely linked with the insulin resistance (IR) syndrome or metabolic syndrome (MetS) [1] and its related comorbidities, including obesity [2], type 2 diabetes mellitus (T2DM) [3], dyslipidemia [4] and cardiovascular disease [5]. The prevalence of NAFLD has been estimated to be about 25%, being higher in selected populations with genetic predisposition (e.g.…”

Section: Introductionmentioning

confidence: 99%

Making progress in nonalcoholic fatty liver disease (NAFLD) as we are transitioning from the era of NAFLD to dys-metabolism associated fatty liver disease (DAFLD)

Polyzos

Mantzoros

2020

Metabolism

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Nonalcoholic fatty liver disease: Updates on associations with the metabolic syndrome and lipid profile and effects of treatment with PPAR-γ agonists

Cited by 19 publications

References 44 publications

Association of Adipokines with Development and Progression of Nonalcoholic Fatty Liver Disease

Association of Adipokines with Development and Progression of Nonalcoholic Fatty Liver Disease

Inflammation is independent of steatosis in a murine model of steatohepatitis

Making progress in nonalcoholic fatty liver disease (NAFLD) as we are transitioning from the era of NAFLD to dys-metabolism associated fatty liver disease (DAFLD)

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