Modulation of hepatic amyloid precursor protein and lipoprotein receptor-related protein 1 by chronic alcohol intake: Potential link between liver steatosis and amyloid-β.

Autor:	Garcia J; Department of Biology, University of La Verne, Verne, CA, United States., Chang R; Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, United States., Steinberg RA; School of Pharmacy and Health Sciences, Keck Graduate Institute, Claremont, CA, United States., Arce A; School of Pharmacy and Health Sciences, Keck Graduate Institute, Claremont, CA, United States., Yang J; Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, United States., Van Der Eb P; School of Pharmacy and Health Sciences, Keck Graduate Institute, Claremont, CA, United States., Abdullah T; Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, United States., Chandrashekar DV; Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, United States., Eck SM; School of Pharmacy and Health Sciences, Keck Graduate Institute, Claremont, CA, United States., Meza P; School of Pharmacy and Health Sciences, Keck Graduate Institute, Claremont, CA, United States., Liu ZX; Department of Molecular Microbiology and Immunology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States., Cadenas E; Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States., Cribbs DH; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA, United States., Kaplowitz N; University of Southern California Research Center for Liver Diseases and Southern California Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States., Sumbria RK; Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, United States.; Department of Neurology, University of California, Irvine, Irvine, CA, United States., Han D; School of Pharmacy and Health Sciences, Keck Graduate Institute, Claremont, CA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in physiology [Front Physiol] 2022 Sep 15; Vol. 13, pp. 930402. Date of Electronic Publication: 2022 Sep 15 (Print Publication: 2022).
DOI:	10.3389/fphys.2022.930402
Abstrakt:	Heavy alcohol consumption is a known risk factor for various forms of dementia and the development of Alzheimer's disease (AD). In this work, we investigated how intragastric alcohol feeding may alter the liver-to-brain axis to induce and/or promote AD pathology. Four weeks of intragastric alcohol feeding to mice, which causes significant fatty liver (steatosis) and liver injury, caused no changes in AD pathology markers in the brain [amyloid precursor protein (APP), presenilin], except for a decrease in microglial cell number in the cortex of the brain. Interestingly, the decline in microglial numbers correlated with serum alanine transaminase (ALT) levels, suggesting a potential link between liver injury and microglial loss in the brain. Intragastric alcohol feeding significantly affected two hepatic proteins important in amyloid-beta (Aβ) processing by the liver: 1) alcohol feeding downregulated lipoprotein receptor-related protein 1 (LRP1, ∼46%), the major receptor in the liver that removes Aβ from blood and peripheral organs, and 2) alcohol significantly upregulated APP (∼2-fold), a potentially important source of Aβ in the periphery and brain. The decrease in hepatic LRP1 and increase in hepatic APP likely switches the liver from being a remover or low producer of Aβ to an important source of Aβ in the periphery, which can impact the brain. The downregulation of LRP1 and upregulation of APP in the liver was observed in the first week of intragastric alcohol feeding, and also occurred in other alcohol feeding models (NIAAA binge alcohol model and intragastric alcohol feeding to rats). Modulation of hepatic LRP1 and APP does not seem alcohol-specific, as ob/ob mice with significant steatosis also had declines in LRP1 and increases in APP expression in the liver. These findings suggest that liver steatosis rather than alcohol-induced liver injury is likely responsible for regulation of hepatic LRP1 and APP. Both obesity and alcohol intake have been linked to AD and our data suggests that liver steatosis associated with these two conditions modulates hepatic LRP1 and APP to disrupt Aβ processing by the liver to promote AD. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Garcia, Chang, Steinberg, Arce, Yang, Van Der Eb, Abdullah, Chandrashekar, Eck, Meza, Liu, Cadenas, Cribbs, Kaplowitz, Sumbria and Han.)
Databáze:	MEDLINE
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