Epidemiological and experimental studies have consistently linked alcoholic beverage consumption with the development of several chronic disorders, such as cancer, cardiovascular diseases, diabetes mellitus and obesity. The impact of drinking is usually dose-dependent, and light to moderate drinking tends to lower risks of certain diseases, while heavy drinking tends to increase the risks. Besides, other factors such as drinking frequency, genetic susceptibility, smoking, diet, and hormone status can modify the association. The amount of ethanol in alcoholic beverages is the determining factor in most cases, and beverage types could also make an influence. This review summarizes recent studies on alcoholic beverage consumption and several chronic diseases, trying to assess the effects of different drinking patterns, beverage types, interaction with other risk factors, and provide mechanistic explanations.

Alcoholic Beverage Consumption and Chronic Diseases

Alcoholic liver disease (ALD) is the number one cause of liver failure worldwide; its management costs billions of healthcare dollars annually. Since the advent of the obesity epidemic, insulin resistance (IR) and diabetes have become common clinical findings in patients with ALD; and the development of IR predicts the progression from simple steatosis to cirrhosis in ALD patients. Both clinical and experimental data implicate the impairment of several mediators of insulin signaling in ALD, and experimental data suggest that insulin-sensitizing therapies improve liver histology. This review explores the contribution of impaired insulin signaling in ALD and summarizes the current understanding of the synergistic relationship between alcohol and nutrient excess in promoting hepatic inflammation and disease.

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Insulin resistance in clinical and experimental alcoholic liver disease.

HNF-4α regulated miR-122 contributes to development of gluconeogenesis and lipid metabolism disorders in Type 2 diabetic mice and in palmitate-treated HepG2 cells.

One of the key event during the development of alcoholic liver disease (ALD) is that alcohol inhibits the insulin signaling pathway in liver and leads to disorders of glucose and lipid metabolism. Methyl ferulic acid (MFA) is a biologically active monomer isolated from the root of Securidaca inappendiculata hasskarl. It has been reported that MFA has a hepatoprotective effect against alcohol-induced liver injury in vivo and in vitro. However, the effect of MFA on ethanol-induced insulin resistance in alcoholic liver disease (ALD) remains unclear. In this study, we investigated whether MFA could exert protective effects against hepatic insulin resistance in ethanol-induced L-02 cells and ALD rats. ALD was induced in vivo by feeding a Lieber-DeCarli diet containing 5% (w/v) alcohol for 16 weeks in Sprague-Dawley rats. Insulin resistance was induced in vitro in human hepatocyte L-02 cells with 200 mM ethanol for 24 h followed by 10-7 nM insulin for 30 min. MFA exhibited the effects of inhibited insulin resistance, reduced the enzymatic capacity for hepatic gluconeogenesis and increased hepatic glycogen synthesis both in vivo and in vitro. In addition, the results of transcriptome sequencing of liver tissues in the ethanol group and MFA-treated group indicated that "pyruvate metabolism", "glycolysis/gluconeogenesis" and "fatty acid metabolism" were significantly different in the ethanol group and MFA-treated group. Further studies suggested that MFA activated the hepatic phosphatidylinositol 3-kinase (PI3K)/AKT pathway in vivo and in vitro. Taken together, these findings suggested that MFA effectively ameliorated hepatic insulin resistance in alcoholic liver disease at least partially through acting on the PI3K/AKT pathway.

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Ethanol-Induced Hepatic Insulin Resistance is Ameliorated by Methyl Ferulic Acid Through the PI3K/AKT Signaling Pathway.

Sepsis is a sustained systemic inflammatory condition involving multiple organ failures caused by dysregulated immune response to infections. Sepsis induces substantial changes in energy demands at the cellular level leading to metabolic reprogramming in immune cells and stromal cells. Although sepsis-associated organ dysfunction and mortality have been partly attributed to the initial acute hyperinflammation and immunosuppression precipitated by a dysfunction in innate and adaptive immune responses, the late mortality due to metabolic dysfunction and immune paralysis currently represent the major problem in clinics. It is becoming increasingly recognized that intertissue and/or intercellular metabolic crosstalk via endocrine factors modulates maintenance of homeostasis, and pathological events in sepsis and other inflammatory diseases. Exosomes have emerged as a novel means of intercellular communication in the regulation of cellular metabolism, owing to their capacity to transfer bioactive payloads such as proteins, lipids, and nucleic acids to their target cells. Recent evidence demonstrates transfer of intact metabolic intermediates from cancer-associated fibroblasts via exosomes to modify metabolic signaling in recipient cells and promote cancer progression. Here, we review the metabolic regulation of endothelial cells and immune cells in sepsis and highlight the role of exosomes as mediators of cellular metabolic signaling in sepsis.

https://www.mdpi.com/1422-0067/22/15/8295/pdf

Cellular and Exosomal Regulations of Sepsis-Induced Metabolic Alterations.

Alcohol is a potential risk factor of type 2 diabetes, but its underlying mechanism is unclear. To explore this issue, Wistar rats and mouse hepatoma cells (Hepa 1–6) were exposed to ethanol, 8 g·kg −1·d −1
for 3 months and 100 mM for 48 h, respectively. Glucose and insulin tolerance tests in vivo were performed, and protein levels of 11 <path id="x1D6FD" d="M558 587q0 -32 -14 -61t-40 -53.5t-48.5 -41t-54.5 -36.5q144 -51 144 -174q0 -55 -43.5 -108t-104.5 -87q-77 -42 -131 -42q-31 0 -54 20t-31 47l11 18q48 -29 108 -29q79 0 119.5 43t40.5 109t-44.5 107.5t-119.5 50.5l22 47q34 1 65 21q96 61 96 157q0 42 -24 67.5
t-62 25.5q-24 0 -43.5 -9t-35 -29.5t-27 -44t-22.5 -63t-19.5 -75.5t-18.5 -91q-57 -294 -68 -380q-26 -190 -35 -200q-26 -31 -97 -37l-4 26q19 9 48 170l77 413q23 121 52.5 187.5t83.5 114.5q70 62 148 62q51 0 88.5 -34t37.5 -91z" /> -hydroxysteroid dehydrogenase type 1 (11 -HSD1) and glucocorticoid receptor (GR) in liver and Hepa 1–6 cells were measured. Alterations of key enzymes of gluconeogenesis phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6 phosphatase (G6Pase), as well as glycogen synthase kinase 3a (GSK3 α), were also examined. The results revealed that glucose levels were increased, and insulin sensitivity was impaired accompanied with liver injury in rats exposed to ethanol compared with controls. The 11 -HSD1, GR, PEPCK, G6Pase, and GSK3 α proteins were increased in the liver of rats treated with ethanol compared with controls. Ethanol-exposed Hepa 1–6 cells also showed higher expression of 11 -HSD1, GR, PEPCK, G6Pase, and GSK3 α proteins than control cells. After treatment of Hepa 1–6 cells exposed to ethanol with the GR inhibitor RU486, the expression of 11 -HSD1 and GR was significantly decreased. At the same time the increases in PEPCK, G6Pase, and GSK3 α levels induced by ethanol in Hepa 1–6 cells were also attenuated by RU486. The results indicate that ethanol causes glucose intolerance by increasing hepatic expression of 11 -HSD1 and GR, which leads to increased expression of gluconeogenic and glycogenolytic enzymes.

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Xueying Bao

Papers

Alteration of 11β-hydroxysteroid dehydrogenase type 1 and glucocorticoid receptor by ethanol in rat liver and mouse hepatoma cells.