Abstract
Alcohol use disorder (AUD) is a chronic relapsing disorder characterized by an impaired ability to control or stop alcohol intake and is associated with organ damage including alcohol-associated liver disease (ALD) and progressive neurodegeneration. The etiology of AUD is complex, but organ injury due to chronic alcohol use can be partially attributed to systemic and local inflammation along the gut-liver-brain axis. Excessive alcohol use can result in translocation of bacterial products into circulation, increased expression of pro-inflammatory cytokines, and activation of immune cells, including macrophages and/or microglia in the liver and brain. One potential mediator of this alcohol-induced inflammation is proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is primarily known for its regulation of plasma low-density lipoprotein cholesterol but has more recently been shown to influence inflammatory responses in the liver and brain. In rodent and post-mortem brain studies, chronic alcohol use altered methylation of the PCSK9 gene and increased expression of PCSK9 in the liver and cerebral spinal fluid. Additionally, PCSK9 inhibition in a rat model of ALD attenuated liver inflammation and steatosis. PCSK9 may play an important role in alcohol-induced pathologies along the gut-liver-brain axis and may be a novel therapeutic target for AUD-related liver and brain inflammation.
Highlights
Excessive alcohol use is a major risk factor for morbidity and mortality, leading to approximately 88,000 deaths in the United States annually
associated liver disease (ALD) is the most prevalent type of chronic liver disease globally. It begins with mild and reversible alcoholic fatty liver and, through constant chronic liver injury and inflammation, can progress to alcoholic steatohepatitis (ASH)/alcoholic hepatitis (AH), alcoholic cirrhosis (AC), and fibrosis, which lead to hepatocellular carcinoma (HCC) and alcoholic hepatic failure [6,7,8,9]
We describe the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in the liver and brain and the effect of alcohol on PCSK9
Summary
Excessive alcohol use is a major risk factor for morbidity and mortality, leading to approximately 88,000 deaths in the United States annually. Acute inflammation acts as an essential protective mechanism against infectious agents and injury by recruiting innate immune cells (neutrophils, monocytes, macrophages, and natural killer (NK) cells) to target tissues to remove damaged cells and promote tissue repair and regeneration. When this acute immune response is impaired due to the persistent presence of injured cells and inflammation, chronic inflammation occurs. We discuss how chronic alcohol exposure affects the development of AUD, ALD, and progressive neurodegeneration and examine the effect of alcohol-induced inflammation along the gut-liver-brain axis. We propose PCSK9 inhibition as a novel therapeutic target to treat ALD and alcohol-induced neurodegeneration
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