Does retinol‐binding protein 4 cause or reflect fatty liver disease?
Authors: Matthias Blüher, Anke Tönjes, Michael Stumvoll
Journal: Hepatology (2008)

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are considered hepatic manifestations of visceral obesity. Clinical and epidemiologic evidence suggests that obesity, type 2 diabetes, and hyperlipidemia are risk factors for NAFLD.1 Likewise, the presence of NAFLD is an indicator of the metabolic syndrome, insulin resistance, and type 2 diabetes.2 NAFLD may progress from simple fat accumulation in hepatocytes to NASH and eventually culminate in advanced fibrosis or cirrhosis.1 In a recent analysis of the multicenter Insulin Resistance Atherosclerosis Study (IRAS), elevated liver enzymes (for example, alanine aminotransferase and aspartate aminotransferase) were shown to predict the risk for metabolic syndrome independent of potentially confounding variables, such as insulin sensitivity and acute insulin response.3 There is increasing evidence that visceral obesity is a causative risk factor for fatty liver and NASH.4 However, the causal mechanisms linking visceral fat accumulation to liver steatosis are still not entirely understood. One potential causal link is the release of nonesterified fatty acids and adipokines from visceral fat into the portal vein directly affecting hepatic substrate and energy metabolism.5 Circulating adipokines are closely related to the occurrence of steatosis and its clinical outcome.4, 6 The etiological importance of adipokines in the pathogenesis of fatty liver disease was demonstrated for several adipokines.6 For example, low adiponectin serum concentrations are associated with NASH7 and adiponectin treatment was shown to reduce liver fat accumulation in mice.8 On the other hand, high circulating levels of leptin, tumor necrosis factor-α, interleukin-6, and others increase fat deposition in the liver6 under specific experimental conditions. HCV, hepatitis C virus; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; RBP-4, retinol-binding protein 4. Taken together, a model arises how dysregulation of adipokine secretion might cause fatty liver disease (Fig. 1). A "two-hit theory" describes the development of NASH and fatty liver cirrhosis. The first hit is an excessive triglyceride accumulation in the liver, which could be caused by increased flux of nonesterified fatty acids and increased secretion of insulin resistance–inducing adipokines from visceral fat (Fig. 1). On the basis of the first hit, oxidative stress as a second hit induces necroinflammation in liver, which further accelerates adipokine dysregulation and insulin resistance. Therefore, normalizing adipokine serum concentrations either by raising reduced (adiponectin) or suppressing elevated adipokines (tumor necrosis factor-α, leptin) would appear to be a promising approach in the treatment of fatty liver diseases. Potential role of RBP4 in mediating the progression of chronic hepatitis C infection and in the metabolic pathway to NASH. RBP4 was suggested as a novel circulating marker for HCV-induced steatosis and could in addition play a role in the metabolic pathway from visceral obesity to insulin resistance and fatty liver disease. Retinol-binding protein 4 (RBP4) has gained a lot of attention after the first notion that it is elevated in the serum of insulin-resistant humans and mice9 and that increased RBP4 serum concentrations are associated with many components of the metabolic syndrome,10 including NAFLD11 and subclinically increased liver fat content determined by magnetic resonance spectroscopy.12 In patients with obesity and type 2 diabetes, RBP4 was shown to be predominantly secreted from visceral adipose tissue.13 However, as of today, a causal link between elevated serum RBP4 and increased fat accumulation in the liver beyond simple association could not be convincingly established. The study by Petta et al.14 confirms the previously recognized association between elevated RBP4 serum concentrations and NAFLD.11, 12 In addition, however, the data of Petta et al.14 shed new light on the relationship—causative versus correlative—of RBP4 and the development of fatty liver disease. The authors demonstrate that independently of obesity and measures of insulin resistance, circulating RBP4 levels are elevated in patients with hepatitis C virus (HCV)-induced steatosis. These results could indicate a direct virus-induced increase in RBP4 levels with subsequent induction of accumulation of fat within hepatocytes providing a novel mechanism for steatosis in HCV infection. Nevertheless, more sophisticated experimental designs will be necessary to conclusively unravel the virus-induced pathways responsible for the association between steatosis and RBP4 in hepatitis C. HCV infection has been shown to cause steatosis through HCV core antigen–related inhibition of mitochondrial beta-oxidation of fatty acids.15 Furthermore, HCV core protein enhances retinoid X receptor-α–dependent transcriptional activity and hepatic overexpression of RBP4,16 representing a different mechanism by which HCV may induce fat deposition in hepatocytes. Moreover, visceral fat accumulation increases accumulation of fat within hepatocytes and accelerates fibrosis in HCV infection.17 Different host and viral factors are involved in the interaction between NAFLD and HCV infection.18 These factors include adipokines, inflammatory cytokines, factors associated with oxidative stress, as well as apoptosis and hepatic stellate cell activation.6, 18 Are there common links between host, viral, and environmental factors that predispose to fatty liver disease or are there a number of unrelated mechanisms all leading to (ectopic) fat deposition? RBP4 could represent such a common link, because circulating RBP4 concentration has been shown to be increased in visceral obesity,13 insulin resistance, and type 2 diabetes,10 as well as in patients with elevated liver fat content.12 Because the liver is the major source of RBP4 secretion in rodents and presumably also in humans,9, 19 elevated circulating RBP4 could simply be a marker of liver fat content independent of the etiology of steatosis. Interestingly, the association between RBP4 levels and liver fat was shown to be independent of insulin resistance, suggesting a relationship between RBP4 levels and liver fat beyond correlation.12 However, adipose tissue is an important source of elevated RBP4 serum concentrations in patients with the metabolic syndrome.13 Therefore, the association between elevated RBP4 and steatosis supports the concept that dysregulation of adipokine secretion from (visceral) fat contributes to both insulin resistance and fatty liver (Fig. 1). Recent experimental data support the hypothesis of a causal role of RBP4 in steatosis. In mice expressing retinoic acid receptor alpha dominant-negative form in hepatocytes, impaired retinoic signaling in the liver leads to hepatic steatosis, suggesting that a primary defect in retinoic signaling in human liver could cause high levels of circulating RBP4, contributing to increased fat accumulation in liver.20 It has been demonstrated that RBP4 can induce the retinoid-regulated gene encoding the gluconeogenic enzyme phosphoenolpyruvate carboxykinase, increase basal glucose production, and reduce insulin action to suppress glucose production in hepatocytes in vitro.9 Moreover, RBP4 treatment in mice impairs suppression of hepatic glucose production in response to maximal insulin concentrations,9 providing another mechanistic link between RBP4-induced insulin resistance, which might lead to increased intracellular fat (Fig. 1). The currently identified association of RBP4 with steatosis in chronic hepatitis C14 adds novel insight into a possible causative role of this molecule in other chronic liver diseases beyond NAFLD. In potential analogy, circulating leptin levels, which closely reflect whole-body fat content, have also been shown to correlate with hepatic steatosis in chronic HCV.21 Similar questions regarding cause or effect relationships can be raised for RBP4 and leptin until further experimental evidence for the mechanistic link between dysregulated adipokine pattern and hepatic steatosis is discovered. The study by Petta et al.14 was not designed to define the temporal relationship between RBP4 and steatosis. Therefore, prospective longitudinal clinical studies may provide further information on the time sequence of elevated RBP4 levels and progression of fatty liver disease. Because it cannot be excluded that adipose tissue is the major source for increased RBP4, we will need to consider RBP4 as an important factor contributing to an impaired communication between visceral adipose tissue and liver in metabolic diseases (Fig. 1). For now, RBP4 can at least be regarded as a promising circulating marker of steatosis both in NAFLD and in chronic hepatitis C.