The burden of hepatocellular carcinoma (HCC), the most common form of liver cancer, is steadily growing because obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD) are replacing viral- and alcohol-related liver disease as major pathogenic promoters. The most worrisome aspects of these new risk factors are their large spread in the general population and their link with HCC arising in noncirrhotic livers. HCC may be the presenting feature of an asymptomatic nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD. The HCC risk connected to metabolic factors has been underestimated so far, and a poorer surveillance has prevented an adequate treatment. Systemic and hepatic molecular mechanisms involved in obesity- and NAFLD-induced hepatocarcinogenesis as well as potential early markers of HCC are being extensively investigated. This review summarizes current evidence linking obesity, NAFLD and liver cancer, discusses its clinical impact and describes the main mechanisms underlyi...

The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of PNPLA3 rs738409, a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort (n = 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of AKR1B10, GDF15, and PDGFA, whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression.

Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD‐NO) compared to those with obesity (NAFLD‐Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD‐NO and 15 NAFLD‐Ob) and 20 CTs without obesity, by gas chromatography–mass spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep‐IR; Hep‐IR = endogenous glucose production × insulin), and the new glutamate–serine–glycine (GSG) index (glutamate/[serine + glycine]) and tested for an association with liver histology. Most AAs were increased only in NAFLD‐Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD‐NO subjects compared to CTs. Glutamate, tyrosine, and the GSG‐index were correlated with Hep‐IR. The GSG‐index correlated with liver enzymes, in particular, gamma‐glutamyltransferase (R= 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG‐index, while only the new GSG‐index was able to discriminate fibrosis F3‐4 from F0‐2 in this cohort.Conclusion: Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism. The GSG‐index is a possible marker of severity of liver disease independent of body mass index. (Hepatology2018;67:145‐158).

Nonalcoholic fatty liver disease (NAFLD) represents an emerging cause of hepatocellular carcinoma (HCC), especially in non-cirrhotic individuals. The rs641738 C > T MBOAT7/TMC4 variant predisposes to progressive NAFLD, but the impact on hepatic carcinogenesis is unknown. In Italian NAFLD patients, the rs641738 T allele was associated with NAFLD-HCC (OR 1.65, 1.08–2.55; n = 765), particularly in those without advanced fibrosis (p < 0.001). The risk T allele was linked to 3’-UTR variation in MBOAT7 and to reduced MBOAT7 expression in patients without severe fibrosis. The number of PNPLA3, TM6SF2, and MBOAT7 risk variants was associated with NAFLD-HCC independently of clinical factors (p < 0.001), but did not significantly improve their predictive accuracy. When combining data from an independent UK NAFLD cohort, in the overall cohort of non-cirrhotic patients (n = 913, 41 with HCC) the T allele remained associated with HCC (OR 2.10, 1.33–3.31). Finally, in a combined cohort of non-cirrhotic patients with chronic hepatitis C or alcoholic liver disease (n = 1121), the T allele was independently associated with HCC risk (OR 1.93, 1.07–3.58). In conclusion, the MBOAT7 rs641738 T allele is associated with reduced MBOAT7 expression and may predispose to HCC in patients without cirrhosis, suggesting it should be evaluated in future prospective studies aimed at stratifying NAFLD-HCC risk.