PPARδ agonist attenuates alcohol-induced hepatic insulin resistance and improves liver injury and repair

Abstract

Background/Aims Chronic ethanol exposure impairs liver regeneration due to inhibition of insulin signaling and oxidative injury. PPAR agonists function as insulin sensitizers and anti-inflammatory agents. We investigated whether treatment with a PPARδ agonist could restore hepatic insulin sensitivity, survival signaling, and regenerative responses vis-a-vis chronic ethanol feeding. Methods Adult rats were fed isocaloric liquid diets containing 0% or 37% ethanol, and administered a PPARδ agonist by i.p. injection. We used liver tissue to examine histopathology, gene expression, oxidative stress, insulin signaling, and regenerative responses to 2/3 hepatectomy. Results Chronic ethanol feeding caused insulin resistance, increased oxidative stress, lipid peroxidation, DNA damage, and hepatocellular injury in liver. These effects were associated with reduced insulin receptor binding and affinity, impaired survival signaling through PI3K/Akt/GSK3β, and reduced expression of insulin responsive genes mediating energy metabolism and tissue remodeling. PPARδ agonist treatment reduced ethanol-mediated hepatic injury, oxidative stress, lipid peroxidation, and insulin resistance, increased signaling through PI3K/Akt/GSK3β, and enhanced the regenerative response to partial hepatectomy. Conclusions PPARδ agonist administration may attenuate the severity of chronic ethanol-induced liver injury and ethanol’s adverse effects on the hepatic repair by restoring insulin responsiveness, even in the context of continued high-level ethanol consumption.

Regulation of Cytochrome P450 2B10 (CYP2B10) Expression in Liver by Peroxisome Proliferator-activated Receptor-β/δ Modulation of SP1 Promoter Occupancy

“…Variation in the expression of these enzymes influences the sensitivity and the adaption to ethanol consumption (13). PPAR␤/␦ can protect against chemically induced liver injury through multiple mechanisms including inhibition of steatosis, inhibition of NF-kB-dependent signaling, and inhibition of inflammation (10,11,16,17). A previous study revealed that exposure to carbon tetrachloride (CCl 4 ) caused an increase in hepatic Cyp2b10 expression, and this induction was mediated by PPAR␤/␦, which was not due to differences in the relative expression of CAR (10), similar to the results observed in the present study.…”

“…Indeed, recent studies have shown that PPAR␤/␦ protects against alcoholic liver disease by inhibiting steatosis, amino acid metabolism, and pyridoxal phosphate activity (8). Similarly, ligand activation of PPAR␤/␦ restores insulin sensitivity and also protects against ethanolinduced liver injury (17 (28). Further studies are needed to delineate the specific activities of PPAR␤/␦ in Kupffer cells and hepatocytes that underlie these differences.…”

“…The facts that PPAR␤/␦ protects against alcoholic liver disease (8,17) and that this protection could be related to the repression of Cyp2b10 following exposure to ethanol are of interest. Therefore, further studies are needed to determine whether this PPAR␤/␦-dependent regulation of Cyp2b10 can be used to identify novel markers of alcoholic liver progression and possibly be suitable for targeting for the prevention and/or treatment of this disease.…”

Hepatocyte Proliferation During Liver Regeneration Is Impaired in Mice with Methionine Diet-Induced Hyperhomocysteinemia

“…29 The inhibition of Akt phosphorylation leads to impaired liver regeneration. 30 We thus determined the phosphorylation of Akt in the liver. The phosphorylation of Akt (Ser473), which results in its activation, was markedly induced within 6 and 12 hours after PH in normal mice.…”

The nuclear receptor CAR modulates alcohol-induced liver injury

“…6,7 On the other hand, several nuclear receptors, PPARa, PPARg, PPARd, RAR, and HNF4a, have been shown to be involved in alcohol-induced liver injury. [8][9][10][11][12] Considering the importance of CAR in P450 enzyme expression and metabolisms of glucose and lipids, we ask whether CAR has a role in modulating alcoholinduced liver injury. In this study, we compared both chronic and acute alcohol-induced liver injury in CAR À/À and wildtype mice.…”