Adiponectin and alcoholic fatty liver: Is it, after all, about what you eat?
Authors: Frank A. Anania
Journal: Hepatology (2005)

This is indeed the beginning of a very exciting era in hepatology as we are making rapid progress in understanding how basic metabolism-related hormones are linked with the pathobiology of hepatic steatosis and liver injury. Because hepatic steatosis is critical to the pathophysiology of both nonalcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease (AFLD); we are on the verge of making substantial breakthroughs in treating two common causes of cirrhosis. The present manuscript by You and colleagues1 provides compelling data related to the increasing importance of adipokines, or adipocytokines, in fatty liver disease, whether related to alcohol or the metabolic syndrome. Of particular excitement is the clairvoyant explanation of how adiponectin mediates the protective role of saturated fatty acids in AFLD. NAFLD, nonalcoholic fatty liver disease; AFLD, alcoholic fatty liver disease; WAT, white adipose tissue; ALT, alanine aminotransferase; HSC, stellate cell; AMPK, AMP-activated kinase; PPAR, peroxisome proliferators activator receptor; PGC-1α, peroxisome proliferator-activated receptor gamma/coactivator-1; PUFA, polyunsaturated fat; HSF, high-saturated fat; CPT, carnitine palmitoyltransferase; siRNA, small interfering RNA. Adiponectin, also known as adipocyte complement-related protein or ACRP 30 is a 30 kd protein hormone that is secreted by white adipose tissue (WAT) such as omental fat.2-4 This adipokine has a plethora of important functions and there is a report that adiponectin has anti-atherogenic potential.5 Its expression and secretion are dramatically decreased in rodent and human obesity and are lower than age- and sex-matched controls in type II diabetes, insulin resistance, and other conditions associated with metabolic syndrome.6 In mice, the administration of adiponectin causes glucose-lowering effects and appears to ameliorate insulin resistance. Unlike leptin, there is no evidence of adiponectin resistance in obesity or metabolic syndrome. Adiponectin may be an attractive therapy for fatty liver disease. Three recent publications provide important background relating the protective effect of adiponectin to various types of liver injury, steatosis, and fibrosis; and these data set the stage for this publication. First, Kamada and colleagues in 2003 demonstrated that liver fibrosis induced by carbon tetrachloride in adiponectin knockout mice was markedly increased compared to that seen in wild-type mice; however, adenoviral expression of adiponectin in the livers of wild-type mice completely prevented carbon tetrachloride-induced fibrosis.7 Xu and colleagues also recently demonstrated in the ob/ob mouse model of nonalcoholic steatohepatitis that overexpression of adiponectin not only significantly improved clinical features of metabolic syndrome but also significantly improved serum alanine aminotransferase (ALT) and reduced lobular inflammatory activity.8 Finally, our group has recently shown that adiponectin has the opposite effects on the biological function of activated hepatic stellate cells9 when compared with leptin.10 Adiponectin suppresses activated stellate cell (HSC) proliferation, sensitizes HSCs to apoptosis, and may prevent the transitional activation from quiescence. Given these recent developments, the present series of experiments presented in this issue provide key insights into how adiponectin may be a molecular link between consumption of dietary saturated fatty acids as a defensive shield against AFLD in mice. Dietary fat content and composition have long been implicated in the pathogenesis of alcoholic liver disease; and diets enriched in saturated fatty acids or medium chain triglycerides protect against alcoholic liver injury. Conversely, diets high in polyunsaturated fatty acids promote liver injury.11, 12 On the other hand, the authors point out that chronic ethanol administration is associated with inhibition of AMP-activated kinase (AMPK), and, peroxisome proliferator activator receptor α (PPARα). Both signaling molecules are key regulatory elements in hepatic fatty oxidation13, 14 and are the major mediators of the metabolic effect of adiponectin.15, 16 The bulk of the data presented results from a standard feeding model using the Lieber-DeCarli diet.17 Male C57/BL/6 mice were equally divided into four dietary groups including (1) polyunsaturated fat pair-fed control diet (PUFA); (2) ethanol-containing polyunsaturated fat diet; (3) a high–saturated fat pair-fed control diet (HSF); and (4) an ethanol-containing high–saturated fat diet. Ethanol did not affect liver triglyceride content when added to the HSF diet, there was no increase in serum ALT, and the circulating adiponectin concentration was increased by nearly twofold; conversely, ethanol feeding in the presence of PUFA resulted in a 4.5-fold increase in serum ALT, a significant increase in hepatic triglyceride content, and a fifteen percent decrease in circulating adiponectin. Additionally, an inverse relationship between circulating concentrations of adiponectin and tumor necrosis factor α was also demonstrated; however, the ethanol-treated mice—regardless of dietary fat composition—sustained significant increases in plasma endotoxin compared with the mice which consumed a control diet. This is an important observation because previous reports indicated that alcohol consumption induced endotoxemia and the effects of alcohol were modulated by the fat composition of the diet.18 The authors demonstrate that ethanol and HSF—but not PUFA and ethanol—resulted in a robust increase in the phosphorylation of AMPKα—the first signaling element whereby the adiponectin receptor activates its respective transduction cascade (See Fig. 1). The authors also demonstrate a significant reduction (54%) of malonyl CoA by HSF in the face of ethanol. Malonyl CoA is a potent inhibitor of carnitine palmitoyltransferase I (CPT I), the rate-limiting step for mitochondrial fatty acid oxidation; the PUFA/ethanol diet enhanced malonyl CoA production, the implication of this process results in inhibition of β-oxidation of fatty acids. The HSF diet in the ethanol-fed mice increased 3-fold acyl-CoA oxidase messenger RNA. Taken together, the HSF diet in the ethanol-fed mice dramatically increased the capacity for hepatic fatty acid β-oxidation and the mice handled fatty acid loads more effectively. The remainder of the paper attempts to elucidate key molecular mechanisms to explain the in vivo findings; although the rather extensive cell culture experiments in hepatocytes fall short of showing a clear and direct link between adiponectin and hepatocyte signal transduction. The authors try to link adiponectin to enhanced fatty acid oxidation by various transfection studies including one which demonstrates adiponectin, in a dose-dependent fashion, significantly increased peroxisome proliferator-activated receptor gamma/coactivator-1 (PGC-1α) promoter activity.19 The rationale for this is clear and is based on the hypothesis that ethanol treatment impairs hepatic fatty acid oxidation by inhibiting the transcriptional activities of PPARα. Adiponectin was shown to increase the reporter activity of PGC-1α in cotransfection experiments; and, PGC-1α is a known coactivator of PPARα.20 Importantly, adiponectin reversed ethanol-associated inhibition of AMPKα phosphorylation, increased the rate of palmitic acid oxidation in isolated rat hepatocytes, and adiponectin secretion was increased in 3T3-L1 adipocytes by either exposure to palmitic or stearic acids in the presence of ethanol. The final experiment using HeLa cells indicates that ethanol and palmitate with stearate, but not palmitate and stearate alone, increase adiponectin promoter reporter activity. Summary of putative functions of adiponectin in protecting hepatocytes from triglyceride accumulation. White adipose tissue (WAT) secretes adiponectin which via the portal circulation eventually binds to adiponectin receptor R 2 (Adipo R2), the predominant receptor isoform in the liver. AdipoR2 activates AMP Kinase (or AMPK) by phosphorylation which has a multitude of effects including a reduction in pro-oxidant products. By contrast, ethanol inhibits AMPK phosphorylation, which according to the authors, is restored in the presence of ethanol by highly saturated fats (HSF). Importantly, adiponectin-associated AMPK activation may result in a net decrease in hepatocyte triglyceride storage by (1) inhibiting genes (e.g., sterol regulatory element-binding protein-1c, SREBP-1c)6 required for de novo free fatty acid synthesis, and (2) by increasing the activity of PPARα resulting in increased β-oxidation of free fatty acids. In this article, the authors show carnitine palmitoyltransferase I (CPT I) activity, the rate-limiting step for mitochondrial fatty acid oxidation, could be enhanced as is the mRNA for acyl-CoA oxidase in hepatocytes treated with ethanol and the HSF diet. Both are associated with increased fatty acid oxidation. The latest work relating adiponectin to AFLD provides a cogent argument whereby saturated fatty acids alleviate AFLD through the upregulation of adiponectin expression. The authors have successfully provided a plausible explanation for previous in vivo observations for a beneficial role adiponectin may play in protection against alcoholic and other types of liver injury. While the present findings are intriguing, this work falls short of a direct link as to exactly how saturated fatty acids—via adiponectin—prevent AFLD. Consequently, the conclusions drawn are speculative. More work on hepatocyte-related adiponectin signaling is now in order to elucidate a causal mechanism. Admittedly, the authors raise these shortcomings, and a compelling paper would have been made even more so if a small interfering RNA (siRNA) for the adiponectin receptor 2 would have been exploited. Because the biology of adiponectin receptors is rapidly developing, such experiments almost certainly will be performed in the near future. Perhaps the HSF diet results in a dramatic increase of adiponectin available to hepatocytes as a result of enhanced production from truncal WAT. The biggest paradox raised in the present work is the danger of human consumption of foods high in saturated fat, as most hepatologists are spending an increasing amount of clinical time these days counseling patients on the dangers of obesity and diabetes. Importantly, modulation of PPARα activity is quite low in humans, and along with the suggestion that nutritional therapy with saturated fatty acids may be beneficial, only underscores how far we have to travel before we can treat AFLD with fat! Perhaps the most promising aspect of this manuscript is that it buttresses the notion that adiponectin is a remedy for both alcoholic and nonalcoholic fatty liver disease and builds on the clear and convincing effects of adipokines in the fundamental biological mechanisms in both hepatocytes and liver nonparenchymal cells. Our current understanding of adiponectin in relationship to hepatocytes is summarized in Fig. 1.