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

Abstract

Background 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.

Ceramide inhibitor myriocin restores insulin/insulin growth factor signaling for liver remodeling in experimental alcohol‐related steatohepatitis

“…27,30 PPAR agonist enhancement of insulin signaling in experimental ALD restores AAH protein expression and hepatic architecture. 4,15,47 Herein, we show similar positive efffects of myriocin on AAH protein in ALD. However, since GSK-3β activation was not significantly modulated by myriocin, the mechanism of enhanced AAH protein expression most likely differed from the effects of PPAR agonists.…”

“…4,8,12 Herein we again demonstrate that chronic ethanol feeding broadly impairs hepatic insulin signaling mechanisms, from receptor to IRS-1, and beyond, including molecules downstream of Akt, specifically PRAS40 and P70S6K. 10,47 Myriocin reduced or abolished most ethanol-associated impairments in insulin signaling, suggesting that in chronic ALD, impairments in insulin signaling are mediated in part by hepatic ceramide accumulation. These findings highlight the importance of targeting dysregulated lipid metabolism and lipotoxicity in the clinical management of ALD.…”

“…Moreover, although insulin sensitizer drugs, such as PPAR agonists 4,47,48 and anti-inflammatory agents, 10 can prevent or reverse many aspects of ALD, their failure to completely resolve the disease process could be due to persistently high levels of hepatic ceramides. 47 The results suggest that monotherapy with ceramide inhibitors can restore hepatic architecture and function in chronic ALD because they normalize hepatic ceramide levels and thereby reduce lipotoxicity, inflammation, and impairments in insulin/IGF-1 signaling and gene expression. Moreover, ceramide inhibitors support signaling through pathways that activate AAH–Notch networks utilized for structural remodeling of the liver after injury.…”

Regulation of glucose and lipid homeostasis by adiponectin: Effects on hepatocytes, pancreatic β cells and adipocytes

“…This may be of particular relevance to fatty liver disease as alcohol impairs AMPK activity in cultured hepatocytes via ceramide-dependent mechanisms (61). Moreover ceramides have been consistently elevated in rodent models of ALD (63–66), and can be lowered by targeted disruption of ceramide formation with imipramine or fumonisin B1, inhibitors of sphingomyelinase or de novo derived ceramide generation, respectively (61). …”

Altered methylation and expression of ER-associated degradation factors in long-term alcohol and constitutive ER stress-induced murine hepatic tumors

“…ER proliferation and liver injury is associated with microsomal alcohol oxidations by CYP2E1 in rats and humans (Cinti et al, 1973; Lieber, 1987). Multiple alcohol consumption-related factors including free radicals, acetaldehyde, toxic lipid species, oxidative stress, excessive homocysteine or S -adenosyl methionine (SAH) from impaired one carbon metabolism, disruption of calcium homeostasis, and insulin resistance are reported to disturb ER homeostasis and induce hepatic ER stress in cultured hepatocytes as well as in the livers of several species including mouse, rat, minipigs, zebrafish, and humans (Ji and Kaplowitz, 2003; Nishitani and Matsumoto, 2006; Passeri et al, 2009; Esfandiari et al, 2010; Magne et al, 2011; Galligan et al, 2012; Kao et al, 2012; Longato et al, 2012; Ramirez et al, 2012, 2013). However, the importance of alcohol-induced ER stress in liver injury may depend on other genetic and environmental factors, patterns of alcohol exposure, and stages of liver disease (Ji, 2012).…”