Ethanol-induced oxidative stress via the CYP2E1 pathway disrupts adiponectin secretion from adipocytes

Adipose tissue is an important target for ethanol action. One important effect of ethanol is to reduce the secretion of adiponectin from adipocytes; this decrease is associated with lowered circulating adiponectin in rodent models of chronic ethanol feeding. Adiponectin is an insulin-sensitizing, anti-inflammatory adipokine; decreased adiponectin activity may contribute to tissue injury in response to chronic ethanol. Here, we investigated the role of cytochrome P450 2E1 (CYP2E1) and oxidative stress in the mechanism for impaired adiponectin secretion from adipocytes in response to ethanol.

Male Wistar rats were fed a liquid diet containing ethanol as 36% of calories or pair-fed a control diet for 4 weeks. 3T3-L1 adipocyte cultures, expressing CYP2E1 or not, were exposed to ethanol or 4-hydroxynonenal (4-HNE).

Chronic ethanol feeding to rats suppressed the secretion of adiponectin from isolated epididymal adipocytes. Ethanol feeding induced the expression of CYP2E1 in adipocytes and increased markers of oxidative stress, including 4-HNE and protein carbonyls. Because adiponectin is posttranslationally processed in the endoplasmic reticulum and Golgi, we investigated the impact of ethanol on the redox status of high-density microsomes. Chronic ethanol decreased the ratio of reduced glutathione to oxidized glutathione (4.6:1, pair-fed; 2.9:1, ethanol-fed) in high-density microsomes isolated from rat epididymal adipose tissue. We next utilized the 3T3-L1 adipocyte-like cell model to interrogate the mechanisms for impaired adiponectin secretion. Culture of 3T3-L1 adipocytes overexpressing exogenous CYP2E1, but not those overexpressing antisense CYP2E1, with ethanol increased oxidative stress and impaired adiponectin secretion from intracellular pools. Consistent with a role of oxidative stress in impaired adiponectin secretion, challenge of 3T3-L1 adipocytes with 4-HNE also reduced adiponectin mRNA expression and secretion, without affecting intracellular adiponectin concentration.

These data demonstrate that CYP2E1-dependent reactive oxygen species production in response to ethanol disrupts adiponectin secretion from adipocytes.