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Misregulation of PPAR Functioning and Its Pathogenic Consequences Associated with Nonalcoholic Fatty Liver Disease in Human Obesity.

Videla LA, Pettinelli P - PPAR Res (2012)

Bottom Line: Nonalcoholic fatty liver disease in human obesity is characterized by the multifactorial nature of the underlying pathogenic mechanisms, which include misregulation of PPARs signaling.Considering that antisteatotic strategies targeting PPAR-α revealed that fibrates have poor effectiveness, thiazolidinediones have weight gain limitations, and dual PPAR-α/γ agonists have safety concerns, supplementation with LCPUFA n-3 appears as a promising alternative, which achieves both significant reduction in liver steatosis scores and a positive anti-inflammatory outcome.This latter aspect is of importance as PPAR-α downregulation associated with LCPUFA n-3 depletion may play a role in increasing the DNA binding capacity of proinflammatory factors, NF-κB and AP-1, thus constituting one of the major mechanisms for the progression of steatosis to steatohepatitis.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Casilla 70000, Santiago 7, Chile.

ABSTRACT
Nonalcoholic fatty liver disease in human obesity is characterized by the multifactorial nature of the underlying pathogenic mechanisms, which include misregulation of PPARs signaling. Liver PPAR-α downregulation with parallel PPAR-γ and SREBP-1c up-regulation may trigger major metabolic disturbances between de novo lipogenesis and fatty acid oxidation favouring the former, in association with the onset of steatosis in obesity-induced oxidative stress and related long-chain polyunsaturated fatty acid n-3 (LCPUFA n-3) depletion, insulin resistance, hypoadiponectinemia, and endoplasmic reticulum stress. Considering that antisteatotic strategies targeting PPAR-α revealed that fibrates have poor effectiveness, thiazolidinediones have weight gain limitations, and dual PPAR-α/γ agonists have safety concerns, supplementation with LCPUFA n-3 appears as a promising alternative, which achieves both significant reduction in liver steatosis scores and a positive anti-inflammatory outcome. This latter aspect is of importance as PPAR-α downregulation associated with LCPUFA n-3 depletion may play a role in increasing the DNA binding capacity of proinflammatory factors, NF-κB and AP-1, thus constituting one of the major mechanisms for the progression of steatosis to steatohepatitis.

No MeSH data available.


Related in: MedlinePlus

Interrelationships between the level of oxidative stress and PPAR-α downregulation in the progression of steatosis to steatohepatitis associated with obesity involving NF-κB (A) and AP-1 (B) signaling. Abbreviations: AP-1: activating protein-1 (c-Jun-cFos; c-Jun-OP, phosphorylated c-Jun); IκB: inhibitor of κB (IκB-OP, phosphorylated IκB); IKK: IκB kinase; JNK: c-Jun N-terminal kinase; LCPUFA, long-chain polyunsaturated fatty acid; NF-κB: nuclear factor-κB (p65-p50); PPAR-α: peroxisome proliferator-activated receptor-α. Solid arrows indicate enhanced contribution, whereas broken arrows indicate reduced contribution.
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fig3: Interrelationships between the level of oxidative stress and PPAR-α downregulation in the progression of steatosis to steatohepatitis associated with obesity involving NF-κB (A) and AP-1 (B) signaling. Abbreviations: AP-1: activating protein-1 (c-Jun-cFos; c-Jun-OP, phosphorylated c-Jun); IκB: inhibitor of κB (IκB-OP, phosphorylated IκB); IKK: IκB kinase; JNK: c-Jun N-terminal kinase; LCPUFA, long-chain polyunsaturated fatty acid; NF-κB: nuclear factor-κB (p65-p50); PPAR-α: peroxisome proliferator-activated receptor-α. Solid arrows indicate enhanced contribution, whereas broken arrows indicate reduced contribution.

Mentions: Liver oxidative stress status, a major mechanism associated with the pathogenesis of steatosis (Figure 1), is exacerbated in obese patients with steatohepatitis (Figure 3). This is evidenced by (i) diminution of hepatic catalase activity, in addition to SOD reduction and GSH depletion already observed in steatosis [57]; (ii) upregulation of the cytochrome P450 2E1 isoform (CYP2E1) and higher in vivo chlorzoxazone hydroxylation catalyzed by CYP2E1, changes that are not observed in steatosis [123]; (iii) further increases in liver nitrotyrosine immunoreactivity [60], hepatic 4-hydroxynonenal (marker of lipid peroxidation) and 8-hydroxydeoxyguanosine (marker of oxidative DNA damage) immunostaining [124], Kupffer-cell-dependent O2•− generation, and lipid peroxidation extent [61] (Figure 3). These changes observed in the liver of steatohepatitis subjects are paralleled by a further decrease in the antioxidant capacity of plasma over that in steatosis [57], which correlates with higher systemic levels of lipid peroxidation products [62, 125–127]. Liver oxidative stress in steatohepatitis is related to several contributory factors, including upregulation of the highly prooxidant CYP2E1 [58, 123, 128], hepatic mitochondrial dysfunction [129, 130], and mixed inflammatory-cell infiltration and Kupffer-cell activation, involving upregulation of NOX2 [61]. The high prooxidant status attained in steatohepatitis was observed concomitantly with significant enhancement in the DNA binding capacity of hepatic nuclear factor-κB (NF-κB) [131, 132] and activating protein 1 (AP-1) [131], redox-sensitive transcription factors that upregulate the expression of proinflammatory mediators at the Kupffer-cell level (Figure 3) [3]. These parameters were not modified in patients with simple steatosis, in relation to controls [131].


Misregulation of PPAR Functioning and Its Pathogenic Consequences Associated with Nonalcoholic Fatty Liver Disease in Human Obesity.

Videla LA, Pettinelli P - PPAR Res (2012)

Interrelationships between the level of oxidative stress and PPAR-α downregulation in the progression of steatosis to steatohepatitis associated with obesity involving NF-κB (A) and AP-1 (B) signaling. Abbreviations: AP-1: activating protein-1 (c-Jun-cFos; c-Jun-OP, phosphorylated c-Jun); IκB: inhibitor of κB (IκB-OP, phosphorylated IκB); IKK: IκB kinase; JNK: c-Jun N-terminal kinase; LCPUFA, long-chain polyunsaturated fatty acid; NF-κB: nuclear factor-κB (p65-p50); PPAR-α: peroxisome proliferator-activated receptor-α. Solid arrows indicate enhanced contribution, whereas broken arrows indicate reduced contribution.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3526338&req=5

fig3: Interrelationships between the level of oxidative stress and PPAR-α downregulation in the progression of steatosis to steatohepatitis associated with obesity involving NF-κB (A) and AP-1 (B) signaling. Abbreviations: AP-1: activating protein-1 (c-Jun-cFos; c-Jun-OP, phosphorylated c-Jun); IκB: inhibitor of κB (IκB-OP, phosphorylated IκB); IKK: IκB kinase; JNK: c-Jun N-terminal kinase; LCPUFA, long-chain polyunsaturated fatty acid; NF-κB: nuclear factor-κB (p65-p50); PPAR-α: peroxisome proliferator-activated receptor-α. Solid arrows indicate enhanced contribution, whereas broken arrows indicate reduced contribution.
Mentions: Liver oxidative stress status, a major mechanism associated with the pathogenesis of steatosis (Figure 1), is exacerbated in obese patients with steatohepatitis (Figure 3). This is evidenced by (i) diminution of hepatic catalase activity, in addition to SOD reduction and GSH depletion already observed in steatosis [57]; (ii) upregulation of the cytochrome P450 2E1 isoform (CYP2E1) and higher in vivo chlorzoxazone hydroxylation catalyzed by CYP2E1, changes that are not observed in steatosis [123]; (iii) further increases in liver nitrotyrosine immunoreactivity [60], hepatic 4-hydroxynonenal (marker of lipid peroxidation) and 8-hydroxydeoxyguanosine (marker of oxidative DNA damage) immunostaining [124], Kupffer-cell-dependent O2•− generation, and lipid peroxidation extent [61] (Figure 3). These changes observed in the liver of steatohepatitis subjects are paralleled by a further decrease in the antioxidant capacity of plasma over that in steatosis [57], which correlates with higher systemic levels of lipid peroxidation products [62, 125–127]. Liver oxidative stress in steatohepatitis is related to several contributory factors, including upregulation of the highly prooxidant CYP2E1 [58, 123, 128], hepatic mitochondrial dysfunction [129, 130], and mixed inflammatory-cell infiltration and Kupffer-cell activation, involving upregulation of NOX2 [61]. The high prooxidant status attained in steatohepatitis was observed concomitantly with significant enhancement in the DNA binding capacity of hepatic nuclear factor-κB (NF-κB) [131, 132] and activating protein 1 (AP-1) [131], redox-sensitive transcription factors that upregulate the expression of proinflammatory mediators at the Kupffer-cell level (Figure 3) [3]. These parameters were not modified in patients with simple steatosis, in relation to controls [131].

Bottom Line: Nonalcoholic fatty liver disease in human obesity is characterized by the multifactorial nature of the underlying pathogenic mechanisms, which include misregulation of PPARs signaling.Considering that antisteatotic strategies targeting PPAR-α revealed that fibrates have poor effectiveness, thiazolidinediones have weight gain limitations, and dual PPAR-α/γ agonists have safety concerns, supplementation with LCPUFA n-3 appears as a promising alternative, which achieves both significant reduction in liver steatosis scores and a positive anti-inflammatory outcome.This latter aspect is of importance as PPAR-α downregulation associated with LCPUFA n-3 depletion may play a role in increasing the DNA binding capacity of proinflammatory factors, NF-κB and AP-1, thus constituting one of the major mechanisms for the progression of steatosis to steatohepatitis.

View Article: PubMed Central - PubMed

Affiliation: Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Casilla 70000, Santiago 7, Chile.

ABSTRACT
Nonalcoholic fatty liver disease in human obesity is characterized by the multifactorial nature of the underlying pathogenic mechanisms, which include misregulation of PPARs signaling. Liver PPAR-α downregulation with parallel PPAR-γ and SREBP-1c up-regulation may trigger major metabolic disturbances between de novo lipogenesis and fatty acid oxidation favouring the former, in association with the onset of steatosis in obesity-induced oxidative stress and related long-chain polyunsaturated fatty acid n-3 (LCPUFA n-3) depletion, insulin resistance, hypoadiponectinemia, and endoplasmic reticulum stress. Considering that antisteatotic strategies targeting PPAR-α revealed that fibrates have poor effectiveness, thiazolidinediones have weight gain limitations, and dual PPAR-α/γ agonists have safety concerns, supplementation with LCPUFA n-3 appears as a promising alternative, which achieves both significant reduction in liver steatosis scores and a positive anti-inflammatory outcome. This latter aspect is of importance as PPAR-α downregulation associated with LCPUFA n-3 depletion may play a role in increasing the DNA binding capacity of proinflammatory factors, NF-κB and AP-1, thus constituting one of the major mechanisms for the progression of steatosis to steatohepatitis.

No MeSH data available.


Related in: MedlinePlus