Chronic alcohol-induced hepatic insulin resistance and endoplasmic reticulum stress ameliorated by peroxisome-proliferator activated receptor-δ agonist treatment.

BACKGROUND AND AIM: Chronic alcoholic liver disease is associated with hepatic insulin resistance, dysregulated lipid metabolism with increased toxic lipid (ceramide) accumulation, lipid peroxidation, and oxidative and endoplasmic reticulum (ER) stress. Peroxisome-proliferator activated receptor (PPAR) agonists are insulin sensitizers that can restore hepatic insulin responsiveness in both alcohol and non-alcohol-related steatohepatitis. Herein, we demonstrate that treatment with a PPAR-δ agonist enhances insulin signaling and reduces the severities of ER stress and ceramide accumulation in an experimental model of ethanol-induced steatohepatitis. METHODS: Adult male Long Evans rats were pair fed with isocaloric liquid diets containing 0% or 37% ethanol (caloric) for 8 weeks. After 3 weeks on the diets, rats were treated with vehicle or PPAR-δ agonist twice weekly by i.p. injection. RESULTS: Ethanol-fed rats developed steatohepatitis with inhibition of signaling through the insulin and insulin-like growth factor-1 receptors, and Akt activated pathways. Despite continued ethanol exposure, PPAR-δ agonist co-treatments increased Akt activation, reduced multiple molecular indices of ER stress and steatohepatitis. CONCLUSIONS: These results suggest that PPAR-δ agonist rescue of chronic alcoholic liver disease is mediated by enhancement of insulin signaling through Akt/metabolic pathways that reduce lipotoxicity and ER stress.

Motor Function Deficits Following Chronic Prenatal Ethanol Exposure are Linked to Impairments in Insulin/IGF, Notch and Wnt Signaling in the Cerebellum.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is associated with deficits in cerebellar function that can persist through adolescence. Previous studies demonstrated striking inhibition of insulin and insulin-like growth factor (IGF) signaling in ethanol-exposed cerebella. OBJECTIVES: We sought to determine if FASD-induced impairments in motor function were associated with deficits in insulin/IGF signaling in juvenile cerebella. Given the growing evidence that insulin/IGF pathways cross-talk with Notch and Wnt to promote brain development and maturation; we also examined the integrity of canonical Wnt and Notch signaling networks in the brain following chronic prenatal ethanol exposure. METHODS: Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 24% ethanol by caloric content from gestation day 6 through delivery. Pups were subjected to rotarod testing on postnatal days (P) 15-16 and sacrificed on P30. Cerebella were used for molecular and biochemical analysis of insulin/IGF-1, canonical Wnt, and Notch signaling mechanisms. RESULTS: Prenatal ethanol exposures impaired rotarod performance, inhibited signaling through insulin and IGF-1 receptors, IRS-1, and Akt, increased activation of GSK-3ß, and broadly suppressed genes mediating the canonical Wnt and Notch networks. CONCLUSIONS: Abnormalities in cerebellar function following chronic prenatal ethanol exposure are associated with inhibition of insulin/IGF, canonical Wnt, and Notch networks that cross-talk via GSK-3ß. Effective therapeutic measures for FASD may require multi-pronged support of interrelated signaling networks that regulate brain development.