Chronic ethanol feeding and folate deficiency activate hepatic endoplasmic reticulum stress pathway in micropigs

Esfandiari, Farah; Villanueva, Jesus A.; Wong, Donna H.; French, Samuel W.; Halsted, Charles H.

doi:10.1152/ajpgi.00542.2004

Cited by 123 publications

(108 citation statements)

References 45 publications

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“…30 Ethanol-induced hyperhomocysteinemia has been proposed to play a role in alcoholic liver injury. 31,32 As shown in Fig. 2D, PUFA ϩ E feeding increased plasma homocysteine by approximately 1.4-fold over PUFA alone, and the HSF ϩ E diet increased homocysteine approximately 2.9-fold as compared with the HSF-fed control animals.…”

Section: A Hsf Diet Attenuated Hepatic Steatosis and Reversed Alaninementioning

confidence: 76%

Role of Adiponectin in the Protective Action of Dietary Saturated Fat Against Alcoholic Fatty Liver in Mice * #

et al. 2005

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The protective effect of dietary saturated fatty acids against the development of alcoholic liver disease has long been known, but the underlying mechanism is not completely understood. We examined the involvement of the adipocyte hormone adiponectin. Circulating adiponectin levels were significantly elevated by chronic ethanol administration to mice consuming a diet high in saturated fat. The increase in circulating adiponectin was associated with the activation a set of hepatic signaling pathways mediated through AMP-activated protein kinase, PPAR-␣, and PPAR-␥ coactivator ␣, which in turn led to markedly increased rates of fatty acid oxidation, prevention of hepatic steatosis, and alleviation of liver enzyme changes. Furthermore, treatment of rat 3T3-L1 adipocytes with saturated fatty acids (palmitic or stearic acids) in the presence of ethanol increased secretion of adiponectin and enhanced activity of a mouse adiponectin promoter. In conclusion, the protective action of saturated fat against the development of alcoholic fatty liver in mice is partially mediated through induction of adiponectin. The present findings suggest a novel paradigm for dietary fatty acids in the pathogenesis of alcoholic liver disease and provide a promising therapeutic strategy-nutritional modulation of adiponectin-in treating human alcoholic fatty liver disease. (HEPATOLOGY 2005;42:568 -577.)

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Section: A Hsf Diet Attenuated Hepatic Steatosis and Reversed Alaninementioning

confidence: 76%

Role of Adiponectin in the Protective Action of Dietary Saturated Fat Against Alcoholic Fatty Liver in Mice * #

et al. 2005

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“…Our prior study showed that folate deficiency had additive effects that were independent of ethanol feeding on markers of liver injury (Esfandiari et al, 2005;Halsted et al, 2002). Therefore, to promote abnormal methionine metabolism while enhancing ER stress and liver injury, all micropigs were placed on folate depleted diets and were divided into 3 different groups (n 5 6) that included: (1) control, (2) ethanol, and (3) ethanol plus SAM at 0.4 g/ 1,000 kcal.…”

Section: Animals and Dietsmentioning

confidence: 99%

“…One hundred milligrams of each liver tissue sample was homogenized, nuclear extracts were prepared, and Western blots were performed as described previously (Esfandiari et al, 2005). Western blot analyses were carried out using multispecies antibodies to SREBP-1c (Santa Cruz Biotechnologies, Santa Cruz, CA), antiAMPKa and b, anti-phospho-AMPKa and b (Cell Signaling Technology, Beverly, MA), and anti-b-actin (1:10,000) (Sigma, St. Louis, MO).…”

Section: Tissue Fractionations and Western Blot Analysismentioning

confidence: 99%

“…Within the methionine metabolic cycle, SAM has the properties of lowering homocysteine while increasing the levels of the antioxidant glutathione (GSH), and it also regulates DNA methylation and nucleotide composition (Halsted, 2004). Other studies, including our own, linked hyperhomocysteinemia and elevated S-adenosylhomocysteine (SAH) levels to hepatic endoplasmic reticulum (ER) stress mechanisms (Esfandiari et al, 2005;Ji and Kaplowitz, 2003), whereas hepatic lipid accumulation and hepatocellular apoptosis in ethanol-fed mice were prevented by betaine, a compound that corrects abnormal methionine metabolism by lowering homocysteine and SAH levels (Ji and Kaplowitz, 2004).…”

mentioning

confidence: 92%

“…Endoplasmic reticulum stress signals including the transcription factor nuclear sterol regulatory element binding protein and its targeted transcripts of acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and steroyl-CoA desaturase (SCD) were activated in the livers of pigs fed the combined ethanol and folatedeficient diet, and their levels were correlated positively to SAH and/or homocysteine (Esfandiari et al, 2005).…”

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confidence: 99%

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S‐Adenosylmethionine Attenuates Hepatic Lipid Synthesis in Micropigs Fed Ethanol With a Folate‐Deficient Diet

Esfandiari

You

Villanueva

et al. 2007

Alcoholism Clin & Exp Res

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Background: To demonstrate a causative role of abnormal methionine metabolism in the pathogenesis of alcoholic steatosis, we measured the effects on hepatic lipid synthesis of supplementing ethanol and folate-deficient diets with S-adenosylmethionine (SAM), a metabolite that regulates methionine metabolism.Methods: Yucatan micropigs were fed folate-deficient diets as control, with ethanol at 40% of kcal, and with ethanol supplemented with SAM at 0.4 g/1,000 kcal for 14 weeks. Histopathology, triglyceride levels and transcripts, and protein levels of the regulatory signals of hepatic lipid synthesis were measured in terminal omental adipose and liver samples.Results: Feeding ethanol at 40% of kcal with folate-deficient diets for 14 weeks increased and supplemental SAM maintained control levels of liver and plasma triglyceride. Serum adiponectin, liver transcripts of adiponectin receptor-1 (AdipoR1), and phosphorylated adenosine monophosphate kinase-b (p-AMPKb) were each reduced by ethanol feeding and were sustained at normal levels by SAM supplementation of the ethanol diets. Ethanol feeding activated and SAM supplementation maintained control levels of ER stress-induced transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) and its targeted transcripts of lipid synthesizing enzymes acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), and glycerol-3-phosphate acyltransferase (GPAT).Conclusions: Ethanol feeding with a folate-deficient diet stimulates hepatic lipid synthesis by down-regulating adiponectin-mediated pathways of p-AMPK to increase the expression of nSREBP1c and its targeted lipogenic enzymes. Preventing abnormal hepatic methionine metabolism by supplementing ethanol diets with SAM reduces liver triglyceride levels by up-regulation of adiponectin-mediated pathways to decrease fatty acid and triglyceride synthesis. This study demonstrates that ethanol-induced hepatic lipid synthesis is mediated in part by abnormal methionine metabolism, and strengthens the concept that altered methionine metabolism plays an integral role in the pathogenesis of steatosis.

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The Kidney in Liver Disease

Levi

2009

The Liver

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Chronic ethanol feeding and folate deficiency activate hepatic endoplasmic reticulum stress pathway in micropigs

Cited by 123 publications

References 45 publications

Role of Adiponectin in the Protective Action of Dietary Saturated Fat Against Alcoholic Fatty Liver in Mice * #

Role of Adiponectin in the Protective Action of Dietary Saturated Fat Against Alcoholic Fatty Liver in Mice * #

S‐Adenosylmethionine Attenuates Hepatic Lipid Synthesis in Micropigs Fed Ethanol With a Folate‐Deficient Diet

The Kidney in Liver Disease

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