Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the main causes of chronic liver disease worldwide. NAFLD comprises a group of conditions characterized by the accumulation of hepatic lipids that can eventually lead to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), the fifth most common cancer type with a poor survival rate. In this context, several works have pointed out perturbations in lipid metabolism and, particularly, changes in bioactive sphingolipids, as a hallmark of NAFLD and derived HCC. In the present work, we have reviewed existing literature about sphingolipids and the development of NAFLD and NAFLD-derived HCC. During metabolic syndrome, considered a risk factor for steatosis development, an increase in ceramide and sphigosine-1-phosphate (S1P) have been reported. Likewise, other reports have highlighted that increased sphingomyelin and ceramide content is observed during steatosis and NASH. Ceramide also plays a role in liver fibrosis and cirrhosis, acting synergistically with S1P. Finally, during HCC, metabolic fluxes are redirected to reduce cellular ceramide levels whilst increasing S1P to support tumor growth.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is a term that encompasses a group of pathologies ranging steatosis, non-alcoholic steatohepatitis (NASH) and cirrhosis (Figure 1)
The aim of this work is to point out the relevance of sphingolipids in the development of NAFLD and NAFLD-derived hepatocellular carcinoma (HCC)
Metabolomics and sphingolipid determination in serum presents an attractive approach for developing diagnostic methods, as these kind of molecules appear to be dysregulated in each pathology
Summary
NAFLD is a term that encompasses a group of pathologies ranging steatosis, non-alcoholic steatohepatitis (NASH) and cirrhosis (Figure 1). This condition is manifested in Western countries, with an incidence rate of about 20%–30% in the general population [1,2]. The most accepted explanation for NAFLD progression is the two-hit hypothesis [3], where an initial first hit induces lipid accumulation in the liver and increases liver vulnerability to different factors (second hits). LLiivveerr ddiisseeaassee pprrooggrreessssiioonn:: ffrroomm sstteeaattoossiiss ttoo hheeppaatotocceelllululalarr cacracricninoomma.a. SScchheemmaattiicc rreepprreesseennttaattiioonn ooffththeetwtwo-oh-hitithyhpyoptohtehseissiasnadntdhethperopgrroegssrieosnsioofnthoef dthiseeadsies,ewasieth, wchiathracchtearriastcitceHris&tiEc Hsta&inEinsgtaimniincgromgriacprohgsrafprohms freoamcheasctahtestaotfe tohfethpeatphaotlhooglyo.gyA. Afirsfitrsht iht itlelaedads saann iinnccrreeaasseedd lliippiidd aaccccuummuullaattiioonn iinn tthhee lliivveerr,, nnaammeedd sstteeaattoossiiss. NAFLD-derived HCC, is mandatory for finding suitable therapies and diagnosing methods against the disease
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