Prevention of Ethanol-Induced Liver Injury in Rats by an Agonist of Peroxisome Proliferator-Activated Receptor-γ, Pioglitazone

Abstract

Agonists of peroxisome proliferator-activated receptor (PPAR)-␥ have been shown to reduce tumor necrosis factor-␣ (TNF-␣)-induced insulin resistance. On the other hand, sensitization of Kupffer cells to lipopolysaccharide (LPS) and their production of TNF-␣ are critical for progression of alcoholic liver injury. This study was intended to determine whether pioglitazone, a PPAR-␥ agonist, could prevent alcohol-induced liver injury. Rats were given ethanol (5 g/kg b.wt.) and pioglitazone (500 g/kg) once every 24 h intragastrically. Ethanol for 8 weeks caused pronounced steatosis, necrosis, and inflammation in the liver. These pathological parameters were diminished greatly by pioglitazone. Kupffer cells were sensitized to LPS after ethanol for 4 weeks as evidenced by aggravation of liver pathology induced by LPS (5 mg/kg) and enhancement of LPS (100 ng/ml)-induced intracellular Ca 2ϩ concentration elevation in Kupffer cells. The parameters were diminished by treatment with pioglitazone. LPS-induced TNF-␣ production by Kupffer cells from the 4-week ethanol group was 3 to 4 times higher than control. This increase was blunted by 70% with pioglitazone. Gut permeability was 10-fold higher in the 4-week ethanol group, and pioglitazone treatment did not change the value. Inclusion of TNF-␣ in culture media of Kupffer cells enhanced CD14 expression, LPS-induced intracellular Ca 2ϩ concentration response, and production of TNF-␣. These results indicate that pioglitazone prevents alcoholic liver injury through abrogation of Kupffer cell sensitization to LPS.

Pioglitazone promotes survival and prevents hepatic regeneration failure after partial hepatectomy in obese and diabetic KK-Ay mice

“…It is also possible that pioglitazone inhibits activation of Kupffer cells independent of adiponectin, because it has also been reported that TZDs inhibit activation of Kupffer cells in a direct manner. 21,22 Taken together, these findings support the hypothesis that the abnormal innate immune responses are critical for the regeneration failure in KK-A y mice.…”

“…33 Because TZDs, synthetic PPAR-␥ ligands, not only improve insulin resistance but also inhibit activation of Kupffer cells 21,22 and transactivation of hepatic stellate cells, [34][35][36] these chemicals are believed to be suitable for prevention/treatment of hepatic inflammation and fibrogenesis in NASH. Indeed, a placebo-controlled randomized study has demonstrated the therapeutic efficacy of pioglitazone on NASH in terms of both metabolic and histological improvement.…”

PPAR gamma inhibits growth of rat hepatic stellate cells and TGF beta-induced connective tissue growth factor expression1

“…PPARγ is a nuclear receptor transcriptional factor and plays an important role in many biological processes, including adipogenesis, cell growth regulation, and cell differentiation. Recent studies have found that thiazolidinediones (TZD) such as pioglitazone and troglitazone, a class of anti-diabetic drugs that function as synthetic ligands of PPARγ with high affinity, inhibit neointima formation in vascular smooth muscle cells in association with decreased DNA synthesis, suggesting that PPARγ may be a potential therapeutic target for the treatment of fibrotic diseases [17][18][19] . In the present study, we extended these observations by determining that PPARγ activation results in the inhibition of HSC growth in a dosedependent manner.…”

Adiponectin and alcoholic fatty liver disease

“…Several lines of investigation have demonstrated that pioglitazone prevents alcohol-induced liver injury in rodents, implying that upregulation of adiponectin by pioglitazone via activation of PPARc may contribute to its hepatic protective effects (49)(50)(51). Although chronic ethanol feeding did not alter adipose mRNA expression of PPARc in animals (11), PPARc ligand binding function could be suppressed by ethanol.…”