The Adverse Effects of Alcohol on Vitamin A Metabolism

The objective of this review is to explore the relationship between alcohol and the metabolism of the essential micronutrient, vitamin A; as well as the impact this interaction has on alcohol-induced disease in adults. Depleted hepatic vitamin A content has been reported in human alcoholics, an observation that has been confirmed in animal models of chronic alcohol consumption. Indeed, alcohol consumption has been associated with declines in hepatic levels of retinol (vitamin A), as well as retinyl ester and retinoic acid; collectively referred to as retinoids. Through the use of animal models, the complex interplay between alcohol metabolism and vitamin A homeostasis has been studied; the reviewed research supports the notion that chronic alcohol consumption precipitates a decline in hepatic retinoid levels through increased breakdown, as well as increased export to extra-hepatic tissues. While the precise biochemical mechanisms governing alcohol’s effect remain to be elucidated, its profound effect on hepatic retinoid status is irrefutable. In addition to a review of the literature related to studies on tissue retinoid levels and the metabolic interactions between alcohol and retinoids, the significance of altered hepatic retinoid metabolism in the context of alcoholic liver disease is also considered

Chronic alcohol consumption decreases brown adipose tissue mass and disrupts thermoregulation: a possible role for altered retinoid signaling

Retinoic acid, an active metabolite of dietary vitamin A, acts as a ligand for nuclear receptor transcription factors with more than 500 known target genes. It is becoming increasingly clear that alcohol has a significant impact on cellular retinoic acid metabolism, with resultant effects on its function. Here, we test the hypothesis that chronic alcohol consumption impairs retinoic acid signaling in brown adipose tissue (BAT), leading to impaired BAT function and thermoregulation. All studies were conducted in age-matched, male mice consuming alcohol-containing liquid diets. Alcohol’s effect on BAT was assessed by histology, qPCR, HPLC, LC/MS and measures of core body temperature. Our data show that chronic alcohol consumption decreases BAT mass, with a resultant effect on thermoregulation. Follow-up mechanistic studies reveal a decreased triglyceride content in BAT, as well as impaired retinoic acid homeostasis, associated with decreased BAT levels of retinoic acid in alcohol-consuming mice. Our work highlights a hitherto uncharacterized effect of alcohol on BAT function, with possible implications for thermoregulation and energy metabolism in drinkers. Our data indicate that alcohol’s effects on brown adipose tissue may be mediated through altered retinoic acid signaling

Distinct Populations of Hepatic Stellate Cells in the Mouse Liver Have Different Capacities for Retinoid and Lipid Storage

Hepatic stellate cell (HSC) lipid droplets are specialized organelles for the storage of retinoid, accounting for 50–60% of all retinoid present in the body. When HSCs activate, retinyl ester levels progressively decrease and the lipid droplets are lost. The objective of this study was to determine if the HSC population in a healthy, uninjured liver demonstrates heterogeneity in its capacity for retinoid and lipid storage in lipid droplets. To this end, we utilized two methods of HSC isolation, which leverage distinct properties of these cells, including their vitamin A content and collagen expression. HSCs were isolated either from wild type (WT) mice in the C57BL/6 genetic background by flotation in a Nycodenz density gradient, followed by fluorescence activated cell sorting (FACS) based on vitamin A autofluorescence, or from collagen-green fluorescent protein (GFP) mice by FACS based on GFP expression from a GFP transgene driven by the collagen I promoter. We show that GFP-HSCs have: (i) increased expression of typical markers of HSC activation; (ii) decreased retinyl ester levels, accompanied by reduced expression of the enzyme needed for hepatic retinyl ester synthesis (LRAT); (iii) decreased triglyceride levels; (iv) increased expression of genes associated with lipid catabolism; and (v) an increase in expression of the retinoid-catabolizing cytochrome, CYP2S1. Conclusion: Our observations suggest that the HSC population in a healthy, uninjured liver is heterogeneous. One subset of the total HSC population, which expresses early markers of HSC activation, may be “primed” and ready for rapid response to acute liver injury

Vitamin A Metabolism: An Update

Retinoids are required for maintaining many essential physiological processes in the body, including normal growth and development, normal vision, a healthy immune system, normal reproduction, and healthy skin and barrier functions. In excess of 500 genes are thought to be regulated by retinoic acid. 11-cis-retinal serves as the visual chromophore in vision. The body must acquire retinoid from the diet in order to maintain these essential physiological processes. Retinoid metabolism is complex and involves many different retinoid forms, including retinyl esters, retinol, retinal, retinoic acid and oxidized and conjugated metabolites of both retinol and retinoic acid. In addition, retinoid metabolism involves many carrier proteins and enzymes that are specific to retinoid metabolism, as well as other proteins which may be involved in mediating also triglyceride and/or cholesterol metabolism. This review will focus on recent advances for understanding retinoid metabolism that have taken place in the last ten to fifteen years

Poor Vitamin Status is Associated with Skeletal Muscle Loss and Mucositis in Head and Neck Cancer Patients

Mucositis and muscle wasting are two common toxicity effects of cancer treatment in head and neck cancer (HNC). There is limited data evaluating cancer treatment toxicities in relation to vitamin status. This study aimed to assess changes in vitamin status during HNC treatment in relation to body composition, inflammation and mucositis. In this prospective cohort study, dietary intakes (3-day food record), plasma levels of vitamins and C-reactive protein (CRP) were assessed at baseline (at diagnosis) and post-treatment (after 6–8 weeks of radiation therapy with or without chemotherapy). Computed tomography images were used to quantify body composition. Mucositis information was collected from health records of patients. Twenty-eight HNC patients (age 60 ± 10 years) completed both study time points. Patients who developed mucositis had significantly lower dietary intake of vitamins and plasma 25-hydroxy vitamin D (25-OHD) and all-trans retinol levels (p < 0.02). Patients lost a considerable amount of muscle mass (3.4 kg) and fat mass (3.6 kg) over the course of treatment. There was a trend toward greater muscle loss in patients with 25-OHD < 50 nmol/L compared to patients with 25-OHD ≥ 50 nmol/L (p = 0.07). A significant negative correlation was found between plasma all-trans retinol and CRP level at the end of treatment (p = 0.03). Poor vitamin status could be a contributing factor in developing treatment-induced toxicities

An Egg White-Derived Peptide Enhances Systemic Insulin Sensitivity and Modulates Markers of Non-Alcoholic Fatty Liver Disease in Obese, Insulin Resistant Mice

Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, is a global health problem. Currently, no pharmacological treatment is approved for NAFLD. Natural health products, including bioactive peptides, are potential candidates to aid in the management of metabolic syndrome-related conditions, including insulin resistance and obesity. In this study, we hypothesized that an egg-white-derived bioactive peptide QAMPFRVTEQE (Peptide 2) would improve systemic and local white adipose tissue insulin sensitivity, thereby preventing high-fat diet-induced exacerbation of pathological features associated with NAFLD, such as lipid droplet size and number, inflammation, and hepatocyte hypertrophy in high-fat diet-fed mice. Similar to rosiglitazone, Peptide 2 supplementation improved systemic insulin resistance during the hyperinsulinemic-euglycemic clamp and enhanced insulin signalling in white adipose tissue, modulating ex vivo lipolysis. In the liver, compared with high-fat diet fed animals, Peptide 2 supplemented animals presented decreased hepatic cholesterol accumulation (p < 0.05) and area of individual hepatic lipid droplet by around 50% (p = 0.09) and reduced hepatic inflammatory infiltration (p < 0.05) whereas rosiglitazone exacerbated steatosis. In conclusion, Peptide 2 supplementation improved insulin sensitivity and decreased hepatic steatosis, unlike the insulin-sensitizing drug rosiglitazone