Chronic alcohol consumption has a biphasic effect on hepatic retinoid loss

Abstract

The alcohol-induced depletion of hepatic retinoid stores correlates with the progression of liver injury; however, the mechanisms underlying alcohol's effects have not been fully elucidated. Our goal was to gain a mechanistic understanding of alcohol-induced hepatic retinoid depletion. Wild-type and mutant mice were continuously fed alcohol through Lieber-DeCarli liquid diets, with matched control animals pair fed an isocaloric alcohol-free diet to ensure equal nutrient and calorie intake between groups. A systematic analysis of tissue retinol and retinyl ester levels was performed with HPLC, complemented by gene and protein expression analyses. Our results delineated 2 phases of alcohol-induced depletion of hepatic retinoid. Initially, ∼15% of hepatic retinoid content was mobilized from the liver, causing extrahepatic tissue retinoid levels to increase. Subsequently, there was a precipitous drop in hepatic retinoid content (>60%), without further retinoid accumulation in the periphery. Follow-up studies in mutant mice revealed roles for RBP, CRBP1, and CD36 in retinoid mobilization and extrahepatic retinoid uptake, as well as a role for CYP2E1 in the catabolism of hepatic retinoid. In summary, alcohol has a biphasic effect on hepatic retinoid stores, characterized by an initial phase of rapid mobilization to extrahepatic tissues followed by extensive catabolism within the liver.

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

“…We have also shown that chronic alcohol consumption has profound effects on tissue retinoid levels, depleting hepatic retinoid levels but driving compensatory increases in other tissues23. To test our working hypothesis that an alcohol-induced disruption of BAT retinoid homeostasis contributed to altered BAT function, we measured BAT retinoid content by HPLC.…”

Cold-mediated regulation of systemic retinol transport controls adipose tissue browning

“…Rbp is well established as a key protein in retinoid metabolism (Quadro, Hamberger, Colantuoni, Gottesman, & Blaner, 2003; Soprano D. R., 1994) mediating retinol secretion and extrahepatic transport preferentially towards adipose tissue as previously demonstrated in Rbp -/- mice challenged with dietary conjugated linoleic acid supplementation or chronic alcohol consumption (Clugston, Huang, & Blaner, 2015; Ortiz et al, 2009). Both studies showed that Rbp facilitates hepatic retinol redistribution towards fat depots although some residual adipose tissue retinol uptake may persist in Rbp deficiency (Clugston et al, 2015) as we observed in BAT of cold-challenged Rbp -/- mice (Fig. 2e).…”

“…Defective BAT retinoid supplies may further aggravate this thermogenic phenotype. In fact, disrupted thermoregulation has previously been reported in alcohol-challenged mice with decreased BAT retinoic acid content (Clugston et al, 2015).…”

Recent insights on the role and regulation of retinoic acid signaling during epicardial development

“…Therefore, it is likely that there are multiple lipases with overlapping expression patterns that can contribute to RE hydrolase activity in vivo. The mechanism of transfer of retinol between liver storage (stellate cells) and liver uptake or secretion sites (hepatocytes) is not understood, but there is evidence that implicates CD36 in the mobilization of hepatic retinoid stores (Clugston, Huang, & Blaner, 2015). The mechanism of transfer of retinol between liver storage (stellate cells) and liver uptake or secretion sites (hepatocytes) is not understood, but there is evidence that implicates CD36 in the mobilization of hepatic retinoid stores (Clugston, Huang, & Blaner, 2015).…”

“…Retinol is secreted from hepatocytes in association with serum retinol binding protein 4 (RBP4), which binds transthyretin (prealbumin) as this complex prevents its renal clearance (Muto, Smith, Milch, & Goodman, 1972;van Jaarsveld, Edelhoch, Goodman, & Robbins, 1973). The mechanism of transfer of retinol between liver storage (stellate cells) and liver uptake or secretion sites (hepatocytes) is not understood, but there is evidence that implicates CD36 in the mobilization of hepatic retinoid stores (Clugston, Huang, & Blaner, 2015). It is also unclear how tissue vitamin A deficient (VAD) status is relayed to the liver to trigger RE hydrolysis and retinol export.…”