Ethanol causes rapid decreases in the hepatic retinoid levels shaping the early steps of alcohol-associated liver disease.

Abstract

Background: Chronic alcohol drinking causes hepatic vitamin A (retinoids and derivatives) decreases, which correlate with the progression and severity of alcohol-associated liver disease (ALD). However, the effects of short-term ethanol (EtOH) intake on liver retinoids and ALD are still undefined.

Methods: Using high-performance liquid chromatography and high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC, HPLC-MS/MS), and molecular biology techniques in mice and cultured human hepatocytes, we investigated the temporal EtOH effects on retinoids and ALD.

Results: In female and male mice, acute EtOH intake caused hepatic retinol (ROL) and retinyl palmitate (RP) decreases within hours, whereas it did not significantly change the retinoic acid (RA) levels, and those of the RA catabolism metabolite, 4-oxo-RA. After EtOH withdrawal, the liver recovered the ROL and RP levels within 48 h, whereas RA and 4-oxo-RA levels remained almost undetectable by this time point. Compared with control diet-fed mice, hepatic ROL and RP levels remained decreased in the 10-day and 3-week-long EtOH treatments, while retinyl oleate and linoleate increased. Interestingly, some of the RA signaling receptors, Rarβ, along with Cyp26a1, revealed dramatic transcript increases during the 10-day-long experiments that attenuated over time (up to 8 weeks), reflecting impaired RA signaling. Our work also showed that primary human hepatocytes serve as a model to better define the role of EtOH in retinoid biology.

Conclusions: This work reveals that acute and short-term exposures to EtOH disrupt retinoid homeostasis, identifying key events in the early pathogenesis of ALD.