Steatosis deLIVERs high sensitivity C-reactive protein

Non-alcoholic fatty liver disease (NAFLD) is characterized by excess accumulation of lipids within parenchymal cells of the liver (i.e., hepatocellular steatosis) in the absence of excessive ethanol consumption. Fatty liver disease is widely considered to be the hepatic manifestation of metabolic syndrome and is estimated to occur in more than 25% of the western population.¹ NAFLD represents a continuum of histopathological and biochemical features progressing from simple steatosis to a more marked inflammatory condition, termed non-alcoholic steatohepatitis (NASH), which potentially causes liver fibrosis.² Basic scientists and clinicians alike are significantly invested in understanding mechanisms underlying the development of steatosis as well as identifying triggers for the transition of simple steatosis to NASH, which contributes significantly to liver-related morbidity. The presence of fatty liver disease in patients has been shown to increase the risk of cardiovascular disease.³ In this issue of ATVB, Ndumele and colleagues identify an association between hepatic steatosis, as assessed by non-invasive abdominal ultrasound, and high sensitivity-C-reactive protein (hs-CRP).⁴ Importantly, this association was independent and additive of obesity and metabolic syndrome. Hs-CRP is an acute phase protein that is an indicator of systemic inflammation and is used clinically to predict adverse cardiovascular events. This observation strongly suggests that inflammation sits at the crossroads between fatty liver disease and cardiovascular disease, highlighting the need for increased scientific engagement across the hepatology, gastroenterology, cardiology and endocrinology fields to better investigate, prevent, and manage these interconnected diseases.

Is fatty liver disease a consequence of increased inflammation, or does inflammation increase hepatic steatosis? The studies of Ndumele and colleagues⁴ provide an association between hepatic steatosis and elevated levels of hs-CRP, a protein produced predominately by the liver under conditions of inflammation. Hepatic steatosis may exaggerate the synthesis of hs-CRP or other mediators by the liver, thereby increasing systemic hs-CRP levels (see Figure). Numerous laboratory studies have shown that inflammation is not simply a consequence of steatosis, but rather its cause. For example, resident macrophages of the liver (i.e., Kupffer cells) are required for hepatic steatosis in mice fed a high fat diet. ^5,6 Moreover, chemokines such as monocyte chemoattractant protein-1 (MCP-1) also contribute to hepatic steatosis.⁷ Thus, in patients with metabolic disease, the inflammatory response likely functions as an amplification loop contributing to hepatic steatosis and systemic change that increases the risk of cardiovascular disease (see Figure). The observation that hepatic steatosis is independently associated with increased hs-CRP levels suggests the possibility that fatty liver disease contributes to cardiovascular disease by promoting an inflammatory response. Studies determining the relative contribution of the fatty liver to the overall systemic inflammatory response in metabolic syndrome will be important. However, the fact that the liver is discretely engaged in a number of metabolic and endocrine processes may present challenges in interpreting the relative contribution of hepatic steatosis.

Figure 1. High sensitivity C-reactive protein at the intersection of hepatology and cardiology in metabolic syndrome.

Ndumele and colleagues⁴ provide evidence of an additive and independent association of hepatic steatosis with high sensitivity C-reactive protein (hs-CRP) levels, suggesting a connection between hepatic steatosis and systemic inflammation determining the risk of cardiovascular disease. Hepatic steatosis (i.e,. fatty liver disease) is the hepatic consequence of metabolic syndrome. The inflammatory microenvironment caused by steatosis leads to both amplification of steatosis and potentially the increased synthesis and release of hs-CRP by the liver. The studies of Ndumele and colleagues⁴ strongly suggest that identifying the mechanism whereby hepatic steatosis contributes to systemic inflammation could yield novel strategies to treat both hepatic and cardiovascular complications of metabolic syndrome.

From a basic liver scientist perspective, the connection between fatty liver disease and cardiovascular disease, such as that presented by Ndumele and colleagues⁴, should shift the paradigm of model selection when studying hepatic steatosis in rodents. Wild type C57Bl/6 mice fed a high fat diet develop hepatic steatosis and are routinely utilized to evaluate the effects of genetic or pharmacologic manipulation on the development of hepatic steatosis. In contrast, hypercholesterolemia and atherosclerosis are most commonly evaluated in mice on this background lacking either the low-density lipoprotein receptor (LDLr) or apolipoprotein E (ApoE). Previous studies have found that fatty liver disease developed in conjunction with hypercholesterolemia and atherosclerosis in LDLr^−/− mice and ApoE^−/− mice, ^8-10 suggesting that these mouse models could be promising for studies evaluating interconnection between these disease processes. Of importance, hepatic inflammation is increased in LDLr^−/− mice compared to wild type C57Bl/6 mice,¹⁰ suggesting that the liver may be a more important contributor to systemic inflammation in these mice than previously thought. Indeed, features of liver disease in LDLr^−/− mice fed a high fat diet resemble those observed in patients with NASH.¹⁰ Insofar as LDLr^−/− mice fed a high fat diet also develop NAFLD/NASH, this mouse model provides ample opportunity to examine the connection between hepatic steatosis and systemic inflammation in the context of numerous features of metabolic syndrome. Identifying interventions that reduce both hepatic steatosis and atherosclerosis in mouse models could pinpoint interactions between these disease processes and lead to the development of new therapies.

In summary, the work of Ndumele and colleagues⁴ is a call for collaboration between basic scientists and clinicians with expertise in fatty liver disease and cardiovascular disease. The association between fatty liver disease and hs-CRP levels strongly suggests that assessing, preventing, and treating NAFLD development is one potential strategy to reduce systemic inflammation and the risk of adverse cardiovascular outcomes in patients with metabolic syndrome.