Altered serum acylcarnitine profile is associated with the status of nonalcoholic fatty liver disease (NAFLD) and NAFLD-related hepatocellular carcinoma

Kenichiro Enooku,Ryosuke Tateishi,Tatsuya Minami,Kazuhiko Koike,Junji Shibahara,Hayato Nakagawa,Naoto Fujiwara,Mayuko Kondo,Yujin Hoshida

doi:10.1038/s41598-019-47216-2

Abstract

Metabolic disturbance of lipids is a hallmark of nonalcoholic fatty liver disease (NAFLD). In this study, we measured the serum levels of 15 acylcarnitine species of various carbon chain lengths from 2 to 18 in 241 patients with biopsy-proven NAFLD, including 23 patients with hepatocellular carcinoma (HCC), and analyzed the relationship between serum acylcarnitine profile and NAFLD status. Long-chain acylcarnitines AC14:1 and AC18:1 increased gradually with the progression of fibrosis and further increased in patients with HCC, whereas the middle-chain acylcarnitine AC5:0 exhibited the opposite trend. In particular, AC18:1, which we previously showed to possess a tumor promoting effect, was significantly elevated in patients with HCC compared to those without HCC. In addition, long-chain acylcarntines including AC18:1 were positively correlated with serum levels of inflammatory cytokines. Although none of the acylcarnitine species were independently associated with the presence of HCC, (AC16:0 + AC18:1)/AC2:0, an index for the diagnosis of carnitine palmitoyltransferase 2 (CPT2) deficiency, was independently associated with the presence of HCC after adjusting for age and liver fibrosis stage, likely reflecting the downregulation of CPT2 in HCC tissues. Thus, serum acylcarnitine profiles changed significantly according to the status of NAFLD, which may be implicated in the pathogenesis of NAFLD.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, affecting 25% of the general population worldwide[1,2]
Serum levels of free carnitine were similar between patients with and without hepatocellular carcinoma (HCC), whereas serum levels of total acylcarnitine were significantly higher in patients with HCC than in those without HCC
We previously reported that serum levels of total acylcarnitine increased according to the progression of fibrosis, and further increased after HCC development in patients with NAFLD10; we analyzed the associations between serum levels of acylcarnitine species and liver fibrosis stage and HCC in this cohort (Fig. 1)

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, affecting 25% of the general population worldwide[1,2]. Hepatic fatty acid β-oxidation (FAO) is impaired in some patients with NAFLD despite increased lipid storage[7]. Such disturbed lipid metabolism causes a marked accumulation of toxic lipids in hepatocytes, leading to lipotoxic cell death, inflammation, subsequent fibrosis, and HCC8,9. Www.nature.com/scientificreports mitochondrial translocation, CPT2 converts acylcarnitine to free carnitine and acyl-CoA, which subsequently enters the FAO pathway. Serum levels of acylcarnitine increased gradually with the progression of fibrosis in patients with NAFLD and further increased in patients with NAFLD and HCC, whereas no such relationship was observed for free carnitine. We measured serum levels of 15 acylcarnitine species of various carbon chain lengths from AC2 to AC18, including unsaturated acylcarnitines, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in a large cohort of 241 biopsy-proven NAFLD patients with and without HCC, and analyzed the relationships between their serum acylcarnitine profiles and NAFLD status

Methods

Results

Conclusion