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Tobacco Smoke-Induced Hepatic Injury with Steatosis, Inflammation, and Impairments in Insulin and Insulin-Like Growth Factor Signaling

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ABSTRACT

Background: Alcoholic liver disease (ALD) is associated with impairments in hepatic insulin and insulin-like growth factor (IGF) signaling through cell growth, survival, and metabolic pathways. Since not all heavy drinkers develop ALD, co-factors may be important. Epidemiologic data indicate that most heavy drinkers smoke tobacco and experimental data revealed that low-level nitrosamine exposures, including those from tobacco, can cause steatohepatitis with hepatic insulin/IGF resistance and exacerbate ALD. We hypothesize that cigarette smoke (CS) exposures also cause liver injury with impaired hepatic insulin/IGF signaling, and thereby contribute to ALD.

Methods: Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 (CS4) or 8 (CS8) weeks, or CS for 8 weeks with 2 weeks recovery (CS8+R).

Results: CS exposures caused progressive liver injury with disruption of the normal hepatic chord architecture, lobular inflammation, apoptosis or necrosis, micro-steatosis, sinusoidal dilatation, and nuclear pleomorphism. Histopathological liver injury scores increased significantly from A8 to CS4 and then further to CS8 (P<0.0001). The mean histological grade was also higher in CS8+R relative to A8 (P<0.0001) but lower than in CS4, reflecting partial resolution of injury by CS withdrawal. CS exposures impaired insulin and IGF-1 signaling through IRS-1, Akt, GSK-3β, and PRAS40. Livers from CS8+R mice had normalized or elevated levels of insulin receptor, pYpY-Insulin-R, 312S-IRS-1, 473S-Akt, S9-GSK-3β, and pT246-PRAS40 relative to A8, CS4, or CS8, reflecting partial recovery.

Conclusion: CS-mediated liver injury and steatohepatitis with impairments in insulin/IGF signalling are reminiscent of the findings in ALD. Therefore, CS exposures (either first or second-hand) may serve as a co-factor in ALD. The persistence of several abnormalities following CS exposure cessation suggests that some aspects of CS-mediated hepatic metabolic dysfunction are not readily reversible.

No MeSH data available.


Related in: MedlinePlus

CS-induced lipid accumulation in hepatocytes. Cryostat sections of liver were stained with Oil Red O to detect neutral lipid (red droplets). Note minimal lipid accumulation in (A) control relative to (B) CS4. (C, D) Oil Red O staining is more diffuse and lower in density but coarser in quality (insets) after 8 weeks of CS exposure, with or without recovery. (Original magnification, 400x).
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Figure 2: CS-induced lipid accumulation in hepatocytes. Cryostat sections of liver were stained with Oil Red O to detect neutral lipid (red droplets). Note minimal lipid accumulation in (A) control relative to (B) CS4. (C, D) Oil Red O staining is more diffuse and lower in density but coarser in quality (insets) after 8 weeks of CS exposure, with or without recovery. (Original magnification, 400x).

Mentions: Oil red O staining revealed minimal or no detectable lipid in control hepatocytes, and small clusters of hepatocytes with abundant fine lipid droplets in CS4 livers. In both the CS8 and CS8+R livers, the intensity of hepatocellular cytoplasmic Oil red O staining was lower but more diffuse relative to CS4 livers. There was no clear difference between CS8 and CS8+R with respect to the density of Oil red O staining, despite different degrees of microsteatosis (Figure 2).


Tobacco Smoke-Induced Hepatic Injury with Steatosis, Inflammation, and Impairments in Insulin and Insulin-Like Growth Factor Signaling
CS-induced lipid accumulation in hepatocytes. Cryostat sections of liver were stained with Oil Red O to detect neutral lipid (red droplets). Note minimal lipid accumulation in (A) control relative to (B) CS4. (C, D) Oil Red O staining is more diffuse and lower in density but coarser in quality (insets) after 8 weeks of CS exposure, with or without recovery. (Original magnification, 400x).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979551&req=5

Figure 2: CS-induced lipid accumulation in hepatocytes. Cryostat sections of liver were stained with Oil Red O to detect neutral lipid (red droplets). Note minimal lipid accumulation in (A) control relative to (B) CS4. (C, D) Oil Red O staining is more diffuse and lower in density but coarser in quality (insets) after 8 weeks of CS exposure, with or without recovery. (Original magnification, 400x).
Mentions: Oil red O staining revealed minimal or no detectable lipid in control hepatocytes, and small clusters of hepatocytes with abundant fine lipid droplets in CS4 livers. In both the CS8 and CS8+R livers, the intensity of hepatocellular cytoplasmic Oil red O staining was lower but more diffuse relative to CS4 livers. There was no clear difference between CS8 and CS8+R with respect to the density of Oil red O staining, despite different degrees of microsteatosis (Figure 2).

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Background: Alcoholic liver disease (ALD) is associated with impairments in hepatic insulin and insulin-like growth factor (IGF) signaling through cell growth, survival, and metabolic pathways. Since not all heavy drinkers develop ALD, co-factors may be important. Epidemiologic data indicate that most heavy drinkers smoke tobacco and experimental data revealed that low-level nitrosamine exposures, including those from tobacco, can cause steatohepatitis with hepatic insulin/IGF resistance and exacerbate ALD. We hypothesize that cigarette smoke (CS) exposures also cause liver injury with impaired hepatic insulin/IGF signaling, and thereby contribute to ALD.

Methods: Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 (CS4) or 8 (CS8) weeks, or CS for 8 weeks with 2 weeks recovery (CS8+R).

Results: CS exposures caused progressive liver injury with disruption of the normal hepatic chord architecture, lobular inflammation, apoptosis or necrosis, micro-steatosis, sinusoidal dilatation, and nuclear pleomorphism. Histopathological liver injury scores increased significantly from A8 to CS4 and then further to CS8 (P<0.0001). The mean histological grade was also higher in CS8+R relative to A8 (P<0.0001) but lower than in CS4, reflecting partial resolution of injury by CS withdrawal. CS exposures impaired insulin and IGF-1 signaling through IRS-1, Akt, GSK-3β, and PRAS40. Livers from CS8+R mice had normalized or elevated levels of insulin receptor, pYpY-Insulin-R, 312S-IRS-1, 473S-Akt, S9-GSK-3β, and pT246-PRAS40 relative to A8, CS4, or CS8, reflecting partial recovery.

Conclusion: CS-mediated liver injury and steatohepatitis with impairments in insulin/IGF signalling are reminiscent of the findings in ALD. Therefore, CS exposures (either first or second-hand) may serve as a co-factor in ALD. The persistence of several abnormalities following CS exposure cessation suggests that some aspects of CS-mediated hepatic metabolic dysfunction are not readily reversible.

No MeSH data available.


Related in: MedlinePlus