Abstract
Sirtuin 1 (SIRT1) is a protein deacetylase with important cellular functions, as it regulates numerous processes, including the circadian rhythm in peripheral tissues. Efforts are ongoing to reveal how Sirt1 can be used to treat diseases, such as alcoholic liver disease (ALD), Alzheimer's disease, and liver fibrosis. We have recently shown that noninvasive exposure to 40-Hz light flicker activates hypothalamic SIRT1 gene expression, thereby regulating the central circadian clock. This study investigated the effects of 40-Hz light flicker in a mouse model of ALD. RNA sequencing (RNA-seq) analysis was performed to explore the potential pathways affected by 40-Hz light flicker. We found that 40-Hz light flicker significantly decreased the acute ethanol-induced increases in serum alanine aminotransferase (ALT) and serum triglyceride (TG) levels and reduced fat-droplet accumulation in mouse livers. Additionally, 40-Hz light flicker significantly suppressed ethanol-induced increases in sterol regulatory element binding protein 1 (SREBP-1) and fatty acid synthase (Fasn) levels. Furthermore, the ethanol induced significant decreases in both Sirt1 levels and phosphorylation of adenosine monophosphate-activated protein kinase subunit (AMPKα), compared with those in the control group. Strikingly, pretreatment with 40-Hz light flicker ameliorated such ethanol-induced decreases in SIRT1 levels and AMPKα phosphorylation. In addition, ethanol-induced increases in levels of brain and muscle arnt-like protein-1 (BMAL1), circadian locomotor output cycles kaput (CLOCK), and period 2 (PER2) were reversed by 40-Hz light flicker. RNA-seq analysis revealed significant differences in expression of genes related to the AMPK signalling. Moreover, ethanol consumption altered mRNA levels of Sirt1 and circadian genes in the suprachiasmatic nucleus (SCN), indicating that ethanol influenced central pacemaker genes; however, 40-Hz light flicker reversed these ethanol-induced changes. Taken together, our findings demonstrate that 40-Hz light flicker rapidly influence the SCN and exhibits inhibitory properties on hepatic lipogenesis, indicating that 40-Hz light flicker has therapeutic potential for preventing alcoholic liver steatosis.
Highlights
The number of patients with chronic liver disease has increased rapidly in recent years (Llorente et al, 2017)
These results reveal that 40-Hz light flicker suppressed the effects of ethanol on hepatic steatosis and lipid metabolism
alcoholic liver disease (ALD) is comprised of a broad spectrum of disorders, ranging from steatosis, alcoholic hepatitis and fibrosis, and even to hepatocellular caner
Summary
The number of patients with chronic liver disease has increased rapidly in recent years (Llorente et al, 2017). Chronic liver diseases, such as cirrhosis and liver cancer, are among the top causes of deaths worldwide (Kim et al, 2014). 50% of all liver-related deaths are related to alcohol (Rehm et al, 2013). Acute alcoholic liver disease (ALD) is caused by excessive intake of alcohol (Gustot and Jalan, 2019). Acute alcoholic fatty liver will develop to hepatic fibrosis, cirrhosis, or even hepatic cancer. There have been no effective treatments for ALD other than alcohol withdrawal. Discovery and development of safe and effective therapies are urgently needed
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