Role of fatty liver, dietary fatty acid supplements, and obesity in the progression of alcoholic liver disease: introduction and summary of the symposium

Abstract

Alcoholic liver disease is a major cause of illness and death in the United States. In the initial stages of the disease, fat accumulation in hepatocytes leads to the development of fatty liver (steatosis), which is a reversible condition. If alcohol consumption is continued, steatosis may progress to hepatitis and fibrosis, which may lead to liver cirrhosis. Alcoholic fatty liver has long been considered benign; however, increasing evidence supports the idea that it is a pathologic condition. Blunting of the accumulation of fat within the liver during alcohol consumption may block or delay the progression of fatty liver to hepatitis and fibrosis. To achieve this goal, it is important to understand the underlying biochemical and molecular mechanisms by which chronic alcohol consumption leads to fat accumulation in the liver and fatty liver progresses to hepatitis and fibrosis. In addition to alcohol consumption, dietary fatty acids and obesity have been shown to affect the degree of fat accumulation within the liver. Again, it is important to know how these factors modulate the progression of alcoholic liver disease. The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements, National Institutes of Health, sponsored a symposium on “Role of Fatty Liver, Dietary Fatty Acid Supplements, and Obesity in the Progression of Alcoholic Liver Disease” in Bethesda, Maryland, USA, October 2003. The following is a summary of the symposium. Alcoholic fatty liver is a pathologic condition that may predispose the liver to further injury (hepatitis and fibrosis) by cytochrome P450 2E1 induction, free radical generation, lipid peroxidation, nuclear factor-kappa B activation, and increased transcription of proinflammatory mediators, including tumor necrosis factor-alpha. Increased acetaldehyde production and lipopolysaccharide-induced Kupffer cell activation may further exacerbate liver injury. Acetaldehyde may promote hepatic fat accumulation by impairing the ability of peroxisome proliferator-activated receptor alpha to bind DNA, and by increasing the synthesis of sterol regulatory binding protein-1. Unsaturated fatty acids (corn oil, fish oil) exacerbate alcoholic liver injury by accentuating oxidative stress, whereas saturated fatty acids are protective. Polyenylphosphatidylcholine may prevent liver injury by down-regulating cytochrome P450 2E1 activity, attenuating oxidative stress, reducing the number of activated hepatic stellate cells, and up-regulating collagenase activity. Nonalcoholic steatohepatitis may develop through several mechanisms, such as oxidative stress, mitochondrial dysfunction and associated impaired fat metabolism, dysregulated cytokine metabolism, insulin resistance, and altered methionine/S-adenosylmethionine/homocysteine metabolism. Obesity (adipose tissue) may contribute to the development of alcoholic liver disease by generating free radicals, increasing tumor necrosis factor-alpha production, inducing insulin resistance, and producing fibrogenic agents, such as angiotensin II, norepinephrine, neuropeptide Y, and leptin. Finally, alcoholic fatty liver transplant failure may be linked to oxidative stress. In vitro treatment of fatty livers with interleukin-6 may render allografts safer for clinical transplantation.

Introduction

Alcoholic liver disease is a major cause of illness and death in the United States. In the initial stages of the disease, fat accumulation in hepatocytes leads to the development of fatty liver (steatosis), which is a reversible condition. If alcohol consumption is continued, steatosis may progress to hepatitis and fibrosis, which may lead to liver cirrhosis.

Alcoholic fatty liver has long been considered benign. However, increasing evidence supports the idea that it is a pathologic condition. This is based on the following features associated with fatty liver that develops in rats in response to chronic administration of the Lieber–DeCarli liquid diet containing 36% alcohol calories:

• Induction of hepatic cytochrome P450 2E1 (CYP2E1) (Lieber, 1999, Ohnishi and Lieber, 1977)

• Increased hepatic concentrations of 4-hydroxynonenal, a marker of lipid peroxidation (Aleynik & Lieber, 2003)

• Increased deposition of iron in the liver (Valerio et al., 1996)

• Selective depletion of hepatic mitochondrial glutathione (GSH), and mitochondrial dysfunction (Garcia-Ruiz et al., 1995, Zhao et al., 2002)

• Depletion of hepatic S-adenosylmethionine (SAMe) (Aleynik & Lieber, 2003)

• Increased serum concentration of tumor necrosis factor-alpha (TNF-α) and increased hepatic expression of TNF-α mRNA levels (Lin et al., 1998)

• Elevated serum alanine aminotransferase concentrations (Gillis and Nagy, 1997, Valerio et al., 1996)

• Increased hepatic concentrations of cellular fibronectin and alpha-smooth muscle actin (Gillis & Nagy, 1997)

Induction of CYP2E1 activity, increased concentrations of 4-hydroxynonenal, increased deposition of iron, and depletion of SAMe and GSH are markers of oxidative stress, which is known to play a pivotal role in the pathogenesis of alcoholic liver disease (Arteel, 2003, Cederbaum et al., 2001, Kaplowitz and Tsukamoto, 1996). Tumor necrosis factor-alpha has been implicated in the pathogenesis of alcohol-induced liver injury in human beings (Bird et al., 1990, Khoruts et al., 1991), as well as in animals (Iimuro et al., 1997, Yin et al., 1999). An increased serum alanine aminotransferase concentration is a marker of hepatic injury. Increased hepatic cellular fibronectin is an early response to injury, and an increased alpha-smooth muscle actin concentration suggests hepatic stellate cell activation, which may result in excessive collagen deposition and subsequent fibrosis.

Despite the pathologic features observed in conjunction with fatty liver, the injury does not progress to inflammation or fibrosis even after administration of the Lieber–DeCarli liquid diet for a long time. This finding supports the notion that a second insult such as lipopolysaccharide stimulation may be required for further progression of liver injury. In fact, simultaneous administration of lipopolysaccharide and the Lieber–DeCarli liquid diet can lead to the development of focal necrotizing hepatitis in rats (Bhagwandeen et al., 1987). Furthermore, in the intragastric infusion model of alcoholic liver injury, lipopolysaccharide plays a central role in the initiation of liver injury by means of activation of Kupffer cells (Adachi et al., 1995, Nanji et al., 1994).

Thus, accumulated fat sensitizes the liver to other toxic agents for further alcoholic injury. Blunting of the accumulation of fat within the liver during alcohol consumption may block or delay the progression of fatty liver to hepatitis and fibrosis. To achieve this goal, it is important to understand the underlying biochemical and molecular mechanisms by which chronic alcohol consumption leads to fat accumulation in the liver. Various mechanisms have been proposed in this regard. Excess hepatic fat accumulation could result from all, some, or a combination of the following:

• Increased fatty acid synthesis

• Decreased fatty acid oxidation

• Increased transport of fatty acids from the peripheral organs to the liver

• Blunted transport of fatty acids from the liver

Further studies are required to understand the molecular mechanisms of alcoholic fatty liver. It is also important to understand the mechanism by which accumulated fat makes the liver susceptible to further injury, such as inflammation and fibrosis. In addition to alcohol, there are many other factors that can contribute to the development of fatty liver that may progress to non-alcoholic steatohepatitis. The presence of non-alcoholic steatohepatitis may further increase the severity of the alcoholic liver injury. Studies are required to understand the interactive effects of non-alcoholic steatohepatitis and alcohol intake on liver injury.

Alcohol consumption seems to affect peripheral fat accumulation, depending on the type of alcoholic beverage consumed, the drinking pattern, and the amount of alcohol consumed. In a study of French people, for whom wine is the most commonly consumed alcoholic beverage, alcohol consumption was associated with a greater waist-to-hip ratio (an indicator of obesity) in both men and women, independent of body mass index (Dallongeville et al., 1998). In another study, beer consumption was positively associated with greater waist-to-hip ratio (Slattery et al., 1992). In yet another study, results showed that drinking intensity (drinks per drinking day) was positively associated, but drinking frequency was inversely associated, with central adiposity (measured by abdominal height) in men and women, supporting the notion that drinking pattern differentially affects central adiposity (Dorn et al., 2003). Thus, on the one hand alcohol consumption can promote obesity. On the other, however, obesity has been reported to increase the risk of fatty liver, hepatitis, and cirrhosis caused by chronic alcohol consumption in human beings (Naveau et al., 1997). In addition, binge drinking increases apoptosis and liver injury in obese rats more so than in lean rats (Carmiel-Haggai et al., 2003). With an understanding of the mechanisms by which alcohol consumption promotes obesity and by which obesity makes the liver more susceptible to alcoholic liver injury, strategies for preventing alcohol-associated accumulation of peripheral fat as well as alcohol-stimulated transport of peripheral fat to the liver may be developed. In turn, through these approaches, the progression of alcoholic liver disease can be blunted.

Dietary fat has been shown to play an important role in the pathogenesis of alcoholic liver disease. Whereas polyunsaturated fatty acids (e.g., omega-6 and omega-3 fatty acids) potentiate the severity of alcoholic liver injury, saturated fatty acids are protective (Nanji et al., 2001, Tsukamoto et al., 1986). In contrast, phospholipids such as phosphatidylcholine (soybean extract) have been shown to prevent alcohol-induced fibrosis and cirrhosis in baboons (Lieber et al., 1994). The toxic effects of polyunsaturated fatty acids are thought to be mediated through increased oxidative stress (lipid peroxidation), whereas the mechanisms of the protective effects of saturated fatty acids and phospholipids are not clear. With an understanding of the underlying molecular mechanisms by which different types of fats potentiate or prevent alcoholic liver injury dietary interventions may be developed for the prevention or treatment of the disease.

In addition to making the liver more susceptible to alcoholic liver injury, hepatic fat affects liver transplant adversely. An understanding of the mechanisms responsible for this effect is important for making fatty liver more acceptable for transplant.

The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements, National Institutes of Health, sponsored a symposium titled and focused on the “Role of Fatty Liver (Steatosis), Dietary Fatty Acids, and Obesity in the Progression of Alcoholic Liver Disease (ALD)” in Bethesda, Maryland, USA, October 2003. For this symposium, nine speakers were invited to address the following issues:

• Fat metabolism and signal transduction

• Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis

• Role of dietary fatty acids in the pathogenesis of alcoholic liver disease

• Molecular mechanisms of alcoholic fatty liver, including the roles of peroxisome proliferator-activated receptor alpha (PPAR-α) and sterol regulatory element-binding proteins (SREBPs)

• Molecular mechanisms of fatty liver transplant failure

• Therapeutic role of interleukin (IL)-6 in alcohol- and obesity-associated fatty liver and fatty liver transplant

• Potential mechanisms of non-alcoholic steatohepatitis

• Obesity and alcoholic liver disease

In the next section, we provide a summary of the papers emanating from this symposium, which were provided by either symposium speakers or session chairs, and published in this Special Issue of Alcohol.