A REPORT BY Murugan and colleagues (2014) in the December issue of ACER provides intriguing data that indicate a central role for hypothalamic b-endorphin (BEP) neurons in influencing the severity and rate of progression of alcoholic liver disease (ALD) and chemically induced (diethylnitrosamine [DEN]) hepatocarcinogenesis. The use and abuse of alcohol has been documented throughout history, and the impact of alcohol in society remains a prominent point of discussion across a broad spectrum of fields, including healthcare (Balakrishnan et al., 2009; Cargiulo, 2007). As with other drugs of abuse and addiction, the effects of alcohol in the brain are central to its continued popularity and use but are, at the same time, the roots of the detrimental effects that arise from its abuse. Equally, the link between chronic, heavy alcohol use and liver damage is well documented (Rehm et al., 2013). Given the long, widespread history of alcohol use (and abuse) it is somewhat surprising that until relatively recently so little was understood about the fundamental mechanisms by which alcohol affects normal behavior and organ function, or how these effects change with “dose” and “time.” Charles Lieber’s seminal work in the 1960s was central to identifying the importance of alcohol metabolism in mediating many of the deleterious effects of alcohol in the liver (Lieber, 2003). These studies initiated our understanding of the importance of hepatic oxidative stress and aldehyde production as hepatotoxins and carcinogens (McKillop and Schrum, 2009) and provided mechanistic evidence to explain differences between those that use alcohol occasionally (metabolism occurs via alcohol dehydrogenase) and those that persistently use alcohol to excess (metabolism occurs via alcohol dehydrogenase and cytochrome P450 2E1 induction; Lieber, 2005). While in retrospect, such studies may seem obvious given the role of the liver in drug metabolism, their importance in changing the approach to studying pathologies associated with alcohol cannot be overstated. As a review of the current alcohol literature reveals, studying the role of alcohol within individual cell types and organs remains critical to understanding how alcohol impacts physiological function and the pathogenesis of a wide range of disease states (McKillop and Schrum, 2005). However, it is clear that such studies must also be considered within the wider context of the local and systemic actions of alcohol and how such systems interact in mediating these events (McKillop and Schrum, 2009). For example, within the context of the liver (an organ for which direct pathological effects of alcohol/alcohol metabolism are known), it is equally important to consider the role of the gut–liver axis in the hepatic response to alcohol consumption, how alcohol alters gut permeability to enteric bacteria, how such changes influence hepatic and systemic immune responses, and how these factors feed back to alter liver function (Szabo and Bala, 2010). Similarly, the role of the liver in sex hormone metabolism impacts the direct and indirect effects of alcohol, both within the liver and in other organ systems (Eagon, 2010), while the effects of alcohol on vascular resistance, angiogenesis, and vascular remodeling can profoundly affect normal and diseased organ function (Cahill and Redmond, 2012). Of course, as we begin to understand the effects of alcohol within these systems and how these events interact, so other factors such as circadian rhythm, diet, nutritional status, age, weight/body mass index, amount and duration of consumption come into play to further compound the complexity of understanding alcohol and disease pathogenesis (Li, 2008). Despite these advances, one clear gap remains to be adequately bridged: that between the brain and the liver, organs for which profound histological, pathological, and functional changes have been most widely reported in the wake of alcohol abuse. Clearly, there is an inextricable link between the biology and pathology of addiction and the “hepatic response” based on the quantity of alcohol consumed, the duration of consumption, and the individual. Increasingly, evidence also indicates the “indirect” effects of alcohol feed back to affect the brain. These include factors such as increased circulating lipopolysaccharide (LPS) levels in chronic, heavy alcohol consumers, and the altered systemic and hepatic immune responses to elevated LPS. These changes in LPS can also affect, and be affected by, factors From the Department of Surgery, Carolinas Medical Center (IHM), Charlotte, North Carolina. Received for publication November 20, 2014; accepted December 9, 2014. Reprint requests: Iain H. McKillop, PhD, Department of Surgery, Cannon Research Center, Rm 402, 1000 Blythe Blvd., Charlotte, NC 28203; Tel.: 704-355-2846; Fax: 704-355-7202; E-mail: firstname.lastname@example.org Copyright© 2015 by the Research Society on Alcoholism.