Liver Hepatokines and Peroxisomes As Therapeutic Targets for Cardiovascular Diseases

Keywords:

• IL-6
• liver–heart communication
• peroxisome

Increasing evidence from recent clinical studies indicates a close connection between liver dysfunction and cardiovascular diseases (CVDs) [1]. Although it remains to be determined how patients with liver diseases develop cardiovascular dysfunction, recent studies using animal models and epidemiology studies have shed light on the key role of hepatokines (a group of liver-derived proteins) and hepatic peroxisome dysfunction in the induction of cardiomyopathy. Here, we summarize the role of representative hepatokines, IL-6 and fetuin-A, and liver peroxisome in the progression of CVDs.

Liver dysfunctions that cause cardiac diseases

Cirrhotic cardiomyopathy

Liver cirrhosis is a well-known cause that alters the systemic hemodynamic system and cardiac function. Cirrhotic cardiomyopathy (CCM) designates a cardiac dysfunction that includes impaired cardiac contractility, systolic and diastolic dysfunction, electromechanical abnormalities in the absence of other known causes of cardiac disease [1]. These cardiac changes can occur in up to 40–50% of patients with cirrhosis, even in children with various liver diseases [2]. Pathogenesis of CCM includes changes in portal pressure and hepatic blood flow, resulting in increased levels of circulating vasodilators, such as adrenomedullin, carbon monoxide, endocannabinoids, nitric oxide and TNF-α [2]. Additionally, downregulation of the density of β-receptors at the cell surface of cardiomyocytes also contributes to the chronotropic incompetence [2]. Current pharmacological treatment for CCM is nonspecific, and directed toward treating cardiac dysfunction or through liver transplantation (LT) [2].

Liver transplantation

In the patients with LT, cardiovascular disease has emerged as the major cause of morbidity and mortality. A meta-analysis of 12 studies concluded that 13.6% of patients who received a liver transplant developed cardiovascular disease, being responsible for 42% of deaths within 30 days following LT [3]. The primary complications of post-LT heart failure include systolic, diastolic or mixed heart failure. These cardiac dysfunctions are caused by the acute hemodynamic changes that are resulted from reperfusion of the graft and pro-inflammatory cytokines [4].

Nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a very common disease in developed countries. Approximately 20–30% of adults in western countries have NAFLD. The prevalence increases from 70 to 90% among people who are obese or have diabetes [5]. The disease can progress toward more serious stages: nonalcoholic steatohepatitis (NASH) and cirrhosis, where inflammation and damage to the liver occur. Beyond the liver-related morbidity and mortality, there is increasing evidence showing that patients with NAFLD are also at high risk of CVD [1]. A recent meta-analysis involving 34,043 adults has shown that patients with NAFLD had a higher risk of fatal and/or nonfatal CVDs comparing with those without NAFLD. Patients with more severe NAFLD were more likely to develop CVDs [6]. Based on the Framingham scoring method, the mean of cardiovascular risks in subjects with and without NAFLD was between 16.0 and 12.7% in men and between 6.7 and 4.6% in women [7]. Manifestations of cardiovascular disease induced by NAFLD include left ventricular dysfunction, atherosclerotic CVDs, ischemic stroke and cardiac arrhythmias. Possible mechanisms include NAFLD-associated insulin resistance, inflammation, visceral adiposity, dyslipidemia and oxidative stress. These studies suggest the close connection between liver health and CVDs.

Aging liver

NAFLD is a common disease in the elderly, in whom it carries a higher chance of developing more serious hepatic diseases (NASH, cirrhosis and hepatocellular carcinoma). Specific aged-related hepatic changes include increased hepatocyte size and the number of binucleated cells, reduction in mitochondrial number, decreased oxidative phosphorylation, impaired peroxisome function [8,9] and upregulation of inflammatory signaling. In addition, aging is associated with a physiological increase in lipid accumulation in the liver and other nonadipose tissues. The association between NAFLD and CVDs is particularly significant in elderly people. Data suggest that in middle-aged individuals (45–54-year-old age group), NAFLD is a strong independent risk factor for cardiovascular mortality [10]. One study evaluated 810 elderly males and 1273 elderly women in Japan and demonstrated that NAFLD was associated with coronary risk factors independent of obesity in either gender [11]. High prevalence of liver diseases and CVDs in the elderly might be a result of inflammaging, a low-grade chronic inflammation that contributes to the aging pathologies. These studies underscore the possibility of liver aging as a causal factor in CVDs.

Hepatokines linked to CVDs

The underlying mechanisms by which liver diseases increase the risk of CVDs has not been fully elucidated. One possible explanation is that intrahepatic inflammation or hepatic damage releases a variety of proatherogenic pro-inflammatory factors, such as hsCRP, fibrinogen, IL-6 and PAI-1. These factors can directly regulate the development of CVDs. Another mechanism is through the secretion of hepatokines that can induce metabolic abnormalities, such as Type 2 diabetes mellitus, hypertriglyceridemia and glucose intolerance, all of which contribute to development of CVDs [12,13].

IL-6

IL-6 is one of the most important proinflammatory cytokines associated with inflammaging and age-related diseases. It is a soluble mediator with a pleiotropic effect on immune response, inflammation and hematopoiesis. Short-term induction of IL-6 signaling can protect myocytes from injury-induced apoptosis. However, prolonged induction of IL-6 signaling can cause pathological hypertrophy and decrease cardiomyocyte contractility through the activation of JAK-STAT pathway. Elevated levels of circulating IL-6 are often associated with myocardial damage, heart failure and atherosclerosis [14]. IL-6 was originally discovered to be secreted primarily from immune cells. However, IL-6 can also be produced from a variety of cell types due to tissue injury or infection, including cardiomyocytes, skeletal muscle and hepatocytes. IL-6 expression is increased in animal models of NAFLD and in the livers of patients with NASH, compared with patients with simple steatosis or normal biopsies [15]. Using Drosophila oenocytes as a hepatocyte model, we recently discovered that the expression of upd3 (the fly homology of mammalian IL-6) in oenocytes increased more than 60-fold during aging. Additionally, we found that reducing oenocyte upd3 expression can effectively restore cardiac arrhythmia during aging [9]. Collectively, these data suggest that increased production of hepatic IL-6 plays an important role in CVDs of NAFLD and NASH patients, as well as in age-associated CVDs.

FetA

FetA is a major carrier protein of free fatty acids. It’s predominantly made in the liver and can be secreted into the bloodstream [16]. Emerging evidence suggests that FetA plays a role in the development of the metabolic syndrome [12], as levels of FetA are increased in NAFLD patients. It is also well-established that the level of FetA is positively associated with insulin resistance [12]. Injection of recombinant FetA into mice can decrease insulin sensitivity, whereas fetuin A deficient mice are insulin sensitive and resistant to weight gain under high fat diet [12]. Given its close association with insulin resistance, it is not surprising that FetA levels are positively associated with markers of early atherosclerosis, incidence of myocardial infarction, ischemic stroke, independent of other cardiovascular risk parameters [17]. A possible mechanism to explain the role of hepatic FetA in insulin resistance and CVDs, is that FetA might serve as a sensor for nutrient level. Under excessive nutrient state, FetA level is increased and is secreted into bloodstream, which contributes to chronic inflammation and metabolic syndrome [18].

The emerging role of hepatic peroxisome dysfunction in cardiomyopathy

Peroxisomes are essential subcellular organelles of all eukaryotic cells that are crucial in the regulation of cellular redox homeostasis, oxidation of very long-chain fatty acids and biosynthesis of ether phospholipid [19]. Impaired peroxisome function often results in disrupted redox homeostasis, elevated lipotoxicity and induction of systemic inflammation [19,20]. Using the fruit fly Drosophila as the model organism, we recently demonstrate a causal role of hepatic peroxisome dysfunction in the nonautonomous regulation of cardiomyopathy and cardiac aging. In the study, we discovered that hepatocyte specific knockdown of peroxisomal import receptor, Pex5, triggers significant production of inflammatory cytokine upd3 (the fly homolog of mammalian IL-6). Notably, either reducing upd3 or overexpressing Pex5 in fly hepatocytes alleviates aging-induced cardiac dysfunction [9]. Our studies provide the first direct evidence supporting the emerging role of hepatic peroxisome function in mediating nonautonomous regulation of cardiac function.

Conclusion

Accumulated evidence from both clinical studies and basic research highlights the importance of liver dysfunction in the development of cardiomyopathy. Hepatokines, which are mainly secreted from the liver, can directly affect glucose, lipid metabolism and modulate inflammatory signaling. All these factors can contribute to the progression of CVDs. Despite the important role of hepatokines in CVDs, how these hepatokines are regulated is less known. Peroxisomes, as well as mitochondria, are highly enriched organelles in the liver. Impaired peroxisomal function may contribute to the induction of hepatokines and the development of CVDs. Therefore, it is critical to develop management strategies and interventions to reduce CVDs risks by targeting liver inflammation, hepatokine secretion and hepatic peroxisome function. Identification of novel hepatokines and biomarkers will assist such development of strategies to treat CVDs.

Author contributions

K Huang researched the data for the article. K Huang and H Bai contributed to the discussion of the content. H Bai and K Huang contributed equally to writing the article, and to reviewing and/or editing of the manuscript before submission.

Financial & competing interests disclosure

The authors would like to a acknowledge the support of NIH/National Institute of Aging (NIA) R01AG058741, and American Heart Association (AHA) Predoctoral Fellowship granted to K Huang (ID: 20PRE35200081). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

The authors would like to a acknowledge the support of NIH/National Institute of Aging (NIA) R01AG058741, and American Heart Association (AHA) Predoctoral Fellowship granted to K Huang (ID: 20PRE35200081). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.