Circulating AIM as an Indicator of Liver Damage and Hepatocellular Carcinoma in Humans

Abstract

BackgroundHepatocellular carcinoma (HCC), the fifth most common cancer type and the third highest cause of cancer death worldwide, develops in different types of liver injuries, and is mostly associated with cirrhosis. However, non-alcoholic fatty liver disease often causes HCC with less fibrosis, and the number of patients with this disease is rapidly increasing. The high mortality rate and the pathological complexity of liver diseases and HCC require blood biomarkers that accurately reflect the state of liver damage and presence of HCC.Methods and FindingsHere we demonstrate that a circulating protein, apoptosis inhibitor of macrophage (AIM) may meet this requirement. A large-scale analysis of healthy individuals across a wide age range revealed a mean blood AIM of 4.99±1.8 µg/ml in men and 6.06±2.1 µg/ml in women. AIM levels were significantly augmented in the younger generation (20s–40s), particularly in women. Interestingly, AIM levels were markedly higher in patients with advanced liver damage, regardless of disease type, and correlated significantly with multiple parameters representing liver function. In mice, AIM levels increased in response to carbon tetrachloride, confirming that the high AIM observed in humans is the result of liver damage. In addition, carbon tetrachloride caused comparable states of liver damage in AIM-deficient and wild-type mice, indicating no influence of AIM levels on liver injury progression. Intriguingly, certain combinations of AIM indexes normalized to liver marker score significantly distinguished HCC patients from non-HCC patients and thus could be applicable for HCC diagnosis.ConclusionAIM potently reveals both liver damage and HCC. Thus, our results may provide the basis for novel diagnostic strategies for this widespread and fatal disease.

A proteolytic modification of AIM promotes its renal excretion

“…This mechanism may prevent a constant increase of the levels of blood AIM, in particular of IgM-free functional AIM. Indeed, we analyzed serum AIM levels in more than 8000 humans (including obese ones exhibiting a body-mass-index >25), and none showed such an increase in AIM levels as observed in obese mice fed a HFD and/or Western diet4. Second, cleavage of AIM modifies its function.…”

“…AIM was initially identified as an apoptosis inhibitor that supports the survival of macrophages against different types of apoptosis-inducing stimuli1. AIM is produced by tissue macrophages under transcriptional regulation by nuclear receptor liver X receptor/retinoid X receptor heterodimers567, and is present at a relatively high level (approximately 5 μg/mL in humans and 2 μg/mL in mice) in blood4. In blood, AIM associates with IgM pentamers, which protects AIM from renal excretion and maintains high levels of circulating AIM8.…”

CD5L is upregulated in hepatocellular carcinoma and promotes liver cancer cell proliferation and antiapoptotic responses by binding to HSPA5 (GRP78)

“…CD5L is also detected in high amounts in serum, where it circulates in association with IgM (12). Moreover, CD5L plasma levels are altered in inflammatory settings, including chronic liver disease (12) in which high serum and plasma levels of CD5L correlate with liver damage, in particular liver fibrosis in HCV and NAFLD (22)(23)(24)(25) and in HCC (26). These significant alterations of plasma CD5L levels, together with the reports suggesting the involvement of this molecule in cancer and HCC, point to a functional role of this protein in liver damage-a question we consider worthy of attention.…”

Translational Nephrology: Taking Aim at Tubular Debris

“…AIM is not detected in the urine of healthy individuals or mice; however protein levels peaked 1 day after IRI and then return to baseline. Although AIM is new to the field as a kidney injury marker, serum AIM has been identified as a potential marker of other inflammatory conditions [24][25][26]. KIM-1 has also received much attention as a biomarker for kidney injury, however despite its identification more than 15 years ago; it has as of yet failed to make the transition into the clinic [12,19,27].…”