Can NASH lipidome provide insight into the pathogenesis of obesity-related non-alcoholic fatty liver disease?
Authors: Aybike Birerdinc, Zobair Younossi
Journal: Journal of Hepatology (2015)

Circulating phospholipid profiling identifies portal contribution to NASH signature in obesityJournal of HepatologyVol. 62Issue 4PreviewNon-alcoholic fatty liver disease (NAFLD) comprises steatosis to non-alcoholic steatohepatitis (NASH). Insulin resistance and obesity are some of the major risk factors for NAFLD [1], along with age [2], gender [3], ethnicity [4,5] and genetic variants such as patatin-like phospholipase domain-containing 3 (PNPLA3) [6]. Incidence of NAFLD in the general population is estimated in the range of 6–14%, whereas in specific population such as in morbid obesity it is reported to be as high as 84–96%, including 25–55% with NASH and 34–47% with liver fibrosis [7]. Full-Text PDF It is estimated that approximately 1 billion people around the world may have Non-Alcoholic Fatty Liver Disease (NAFLD) with a prevalence of 20–30% in Western countries [1Machado M.V. Cortez-Pinto H. Non-alcoholic fatty liver disease: what the clinician needs to know.World J Gastroenterol. 2014; 20 (PubMed PMID: 25278691; PubMed Central PMCID: PMC4177476): 12956-12980https://doi.org/10.3748/wjg.v20.i36.12956Crossref PubMed Scopus (132) Google Scholar, 2Milić S. Stimac D. Nonalcoholic fatty liver disease/steatohepatitis: epidemiology, pathogenesis, clinical presentation and treatment.Dig Dis. 2012; 30 (Review. PubMed PMID: 22722431): 158-162https://doi.org/10.1159/000336669Crossref PubMed Scopus (150) Google Scholar, 3Mouzaki M. Allard J. Non-alcoholic steatohepatitis: the therapeutic challenge of a global epidemic.Ann Gastroenterol. 2012; 25 (Review. PubMed PMID: 24713803; PubMed Central PMCID: PMC3959359): 207-217Google Scholar]. Obesity is both the most common predictor of NAFLD and the most rapidly growing health concern in the world [[4]World Health Organization. Global status report on non communicable diseases; 2014.Google Scholar]. The growing number of people, of all ages, who currently have NAFLD and the estimates of those that will develop this condition based on the projected rates of obesity, urgently necessitates numerous lines of research focusing on the diagnosis and effective treatment of NAFLD. Since NAFLD is so intricately correlated with insulin resistance and obesity, a natural and surprisingly understudied area of NAFLD research is the study of the changes in the lipid composition of biological fluids and relevant tissues through the exploration of a broad field commonly known as: lipidomics. It is evident that the changes in the lipid profiles within the liver, the adipose tissue and the plasma, accompany NAFLD, however, the contribution of these changes to the pathogenesis of this disease remain enigmatic [[5]Ferolla S.M. Armiliato G.N. Couto C.A. Ferrari T.C. The role of intestinal bacteria overgrowth in obesity-related nonalcoholic fatty liver disease.Nutrients. 2014; 6 (Review. PubMed PMID: 25479248): 5583-5599Crossref PubMed Scopus (70) Google Scholar]. In the current paper titled "Circulating phospholipid profiling identifies portal contribution to NASH signature in obesity," Anjani and colleagues used mass spectrometry-based lipidomic analysis to dissect this so-called Non-Alcoholic Steatohepatitis (NASH) "signature" in a cohort of 46 morbidly obese women. The study simultaneously profiled several types of samples, including the venous blood specimens collected before and 12 months post bariatric surgery and quantified the lipid efflux in portal blood and adipose tissue at the time of surgery. A total of 9 structural classes and 150 species of lipids were analyzed in the hope to distinguish the subspecies of the lipids that correlate most closely with liver disease status. In the systemic blood specimens of NASH subjects as compared to that of non-NASH subjects, the authors reported an increase in the concentration of a variety of classes of lipids. Interestingly, in patients who achieved weight loss 12 months after bariatric surgery, the levels of liver enzymes normalized along with a number of lipid species, however, a majority of glycerophosphoglycerols (PG) and ceramide (Cer) species continued to be elevated. Further analysis of the lipids isolated from the hepatic portal system indicated a minimal variance from those seen in the systemic circulation, with the exception of PG and glycerophosphoethanolamines (PE) classes which were substantially elevated in the NASH cohort. Notably, when the authors assessed the involvement of visceral adipose tissue to this circulating lipid profile by measuring adipose tissue lipid efflux ex vivo, only minor differences were detected between the NASH and the non-NASH cohorts. Most interestingly, a Bayesian network analysis of the lipid profiles from the hepatic portal system, a known conduit for molecules from the visceral organs to the liver, revealed a high correlation between glycerophosphocholines (PC) (40:4) and NASH, while sphingomyelins (SM) (42:3) and a short chain (C14) Cer were decreased in the portal circulation of NASH subjects. Heat map visualization also showed NASH-specific alterations in lipid profiles of the hepatic portal circulation. Notably, the best NASH signature the authors could obtain was by integrating clinical and lipidomic data, both portal and systemic, where all lipids and clinical parameters were given equal weight. The authors concluded that visceral adipose contributing to overall lipidome was secondary to that of other sources of the drainage into the hepatic portal system, for example, the gut. While this is by no means a novel suggestion in the field of NASH [5Ferolla S.M. Armiliato G.N. Couto C.A. Ferrari T.C. The role of intestinal bacteria overgrowth in obesity-related nonalcoholic fatty liver disease.Nutrients. 2014; 6 (Review. PubMed PMID: 25479248): 5583-5599Crossref PubMed Scopus (70) Google Scholar, 6Festi D. Schiumerini R. Eusebi L.H. Marasco G. Taddia M. Colecchia A. Gut microbiota and metabolic syndrome.World J Gastroenterol. 2014; 20 (Review. PubMed PMID: 25473159): 16079-16094Crossref PubMed Scopus (337) Google Scholar, 7Paolella G. Mandato C. Pierri L. Poeta M. Di Stasi M. Vajro P. Gut-liver axis and probiotics: their role in non-alcoholic fatty liver disease.World J Gastroenterol. 2014; 20 (Review. PubMed PMID: 25400436; PubMed Central PMCID: PMC4229517): 15518-15531Crossref PubMed Scopus (143) Google Scholar], the exact mechanism of this contribution has yet to be demonstrated. It is interesting to note that from a histological perspective both PE and PC classes of lipids have been shown to be decreased in liver tumors as compared to normal tissue [[8]Bell J.D. Cox I.J. Sargentoni J. Peden C.J. Menon D.K. Foster C.S. et al.A 31P and 1H-NMR investigation in vitro of normal and abnormal human liver.Biochim Biophys Acta. 1993; 1225 (PubMed PMID: 8241291): 71-77Crossref PubMed Scopus (97) Google Scholar]. Moreover, in liver regeneration following hepatic resection, the decrease in the levels of both PE and PC was observed [[9]Zakian K.L. Koutcher J.A. Malhotra S. Thaler H. Jarnagin W. Schwartz L. et al.Liver regeneration in humans is characterized by significant changes in cellular phosphorus metabolism: assessment using proton-decoupled 31P-magnetic resonance spectroscopic imaging.Magn Reson Med. 2005; 54 (PubMed PMID: 16032692): 264-271Crossref PubMed Scopus (18) Google Scholar], which may also explain the disappearance of hepatic triacylglycerol (TAG) in the histopathological progression of NAFLD from steatosis, to early fibrosis and then to cirrhosis. However, much less is known about the circulating species of these lipids and their direct contribution to NAFLD pathogenesis and progression. Perhaps more mechanistically relevant to NAFLD, Gugliucci et al. were able to demonstrate that low-density lipoprotein (LDL) glycation is a predisposing event to subsequent oxidative modification. Most interestingly, LDL and very-low-density lipoprotein (VLDL) fractions of diabetic patients are much more susceptible to oxidation [[10]Gugliucci A. Menini T. Stahl A.J. Susceptibility to copper-enhanced autoxidation of VLDL+LDL fractions from diabetic patients.Biochem Mol Biol Int. 1994; 32: 139-147PubMed Google Scholar]. In turn, lipid oxidation has been shown to increase the uptake of LDL particles by macrophages [[11]Hunt J.V. Bottoms M.A. Clare K. Skamarauskas J.T. Mitchinson M.J. Glucose oxidation and low-density lipoprotein-induced macrophage ceroid accumulation: possible implications for diabetic atherosclerosis.Biochem J. 1994; 300: 243-249Crossref PubMed Scopus (59) Google Scholar], with the glucosylated PE being the major LDL lipid glycation products [[12]Ravandi A. Kuksis A. Shaikh N.A. Glucosylated glycerophosphoethanolamines are the major LDL glycation products and increase LDL susceptibility to oxidation: evidence of their presence in atherosclerotic lesions.Arterioscler Thromb Vasc Biol. 2000; 20 (PubMed PMID: 10669645): 467-477Crossref PubMed Scopus (69) Google Scholar]. From a more global perspective, one may assume that an increase in BMI leads to a larger influx of nonesterified fatty acids (NEFAs) to the liver, thus, causing elevation of their levels in the portal blood of NASH subjects, reflecting a compensatory feedback against oxidative stress [[13]Barr J. Caballería J. Martínez-Arranz I. Domínguez-Díez A. Alonso C. Muntané J. et al.Obesity-dependent metabolic signatures associated with nonalcoholic fatty liver disease progression.J Proteome Res. 2012; 11 (Epub. PubMed PMID: 22364559; PubMed Central PMCID: PMC3321123): 2521-2532https://doi.org/10.1021/pr201223pCrossref PubMed Scopus (159) Google Scholar]. Following this logic, with more progression along the path to steatosis, lower levels of PE and PG along with higher Cer and SM species should be observed as the balance shifts towards hepatotoxic lipid species. Hence, this study of Anjani and colleagues opens a Pandora's box of possible interpretations. Nevertheless, this current study takes an important step towards understanding some of the key players in the mechanisms triggering and propagating NASH in obese women. It is important to mention that the relatively small sample size limits the generalizability of these findings. Nevertheless, the in-depth lipidomic assessment provides some intriguing data about the pathogenesis of NAFLD spectrum in obese individuals. Future studies need to delve deeper into lipidomics, in larger cohorts of both genders, properly controlled for medications, especially lipid-lowering agents that may affect the outcomes [14Tziomalos K. Lipid-lowering agents in the management of nonalcoholic fatty liver disease.World J Hepatol. 2014; 6 (Review. PubMed PMID: 25349644; PubMed Central PMCID: PMC4209418): 738-744https://doi.org/10.4254/wjh.v6.i10.738Crossref PubMed Scopus (19) Google Scholar, 15Aung L.H. Yin R.X. Wu D.F. Wang W. Wu J.Z. Liu C.W. Sex-specific association of the zinc finger protein 259 rs2075290 polymorphism and serum lipid levels.Int J Med Sci. 2014; 11 (eCollection. PubMed PMID: 24688311; PubMed Central PMCID: PMC3970100.): 471-478https://doi.org/10.7150/ijms.8489Crossref PubMed Scopus (15) Google Scholar]. Anjani et al. have taken an important step towards unraveling the tangled threads of the obesity and NASH axis that warrant more pathogenetic insights into metabolic syndrome and associated conditions, which are rapidly becoming the largest health burden on the Western world health care system. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. All authors contributed equally to manuscript preparation.