UNASSIGNED: Progression of alcohol-associated liver disease (ALD) is driven by genetic predisposition. The rs13702 variant in the lipoprotein lipase (LPL) gene is linked to non-alcoholic fatty liver disease. We aimed at clarifying its role in ALD.
UNASSIGNED: Patients with alcohol-associated cirrhosis, with (n = 385) and without hepatocellular carcinoma (HCC) (n = 656), with HCC attributable to viral hepatitis C (n = 280), controls with alcohol abuse without liver damage (n = 366), and healthy controls (n = 277) were genotyped regarding the LPL rs13702 polymorphism. Furthermore, the UK Biobank cohort was analysed. LPL expression was investigated in human liver specimens and in liver cell lines.
UNASSIGNED: Frequency of the LPL rs13702 CC genotype was lower in ALD with HCC in comparison to ALD without HCC both in the initial (3.9% vs. 9.3%) and the validation cohort (4.7% vs. 9.5%; p <0.05 each) and compared with patients with viral HCC (11.4%), alcohol misuse without cirrhosis (8.7%), or healthy controls (9.0%). This protective effect (odds ratio [OR] = 0.5) was confirmed in multivariate analysis including age (OR = 1.1/year), male sex (OR = 3.0), diabetes (OR = 1.8), and carriage of the PNPLA3 I148M risk variant (OR = 2.0). In the UK Biobank cohort, the LPL rs13702 C allele was replicated as a risk factor for HCC. Liver expression of LPL mRNA was dependent on LPL rs13702 genotype and significantly higher in patients with ALD cirrhosis compared with controls and alcohol-associated HCC. Although hepatocyte cell lines showed negligible LPL protein expression, hepatic stellate cells and liver sinusoidal endothelial cells expressed LPL.
UNASSIGNED: LPL is upregulated in the liver of patients with alcohol-associated cirrhosis. The LPL rs13702 high producer variant confers protection against HCC in ALD, which might help to stratify people for HCC risk.
UNASSIGNED: Hepatocellular carcinoma is a severe complication of liver cirrhosis influenced by genetic predisposition. We found that a genetic variant in the gene encoding lipoprotein lipase reduces the risk for hepatocellular carcinoma in alcohol-associated cirrhosis. This genetic variation may directly affect the liver, because, unlike in healthy adult liver, lipoprotein lipase is produced from liver cells in alcohol-associated cirrhosis.

Glycolipid metabolism disorder are major threats to human health and life. Genetic, environmental, psychological, cellular, and molecular factors contribute to their pathogenesis. Several studies demonstrated that neuroendocrine axis dysfunction, insulin resistance, oxidative stress, chronic inflammatory response, and gut microbiota dysbiosis are core pathological links associated with it. However, the underlying molecular mechanisms and therapeutic targets of glycolipid metabolism disorder remain to be elucidated. Progress in high-throughput technologies has helped clarify the pathophysiology of glycolipid metabolism disorder. In the present review, we explored the ways and means by which genomics, transcriptomics, proteomics, metabolomics, and gut microbiomics could help identify novel candidate biomarkers for the clinical management of glycolipid metabolism disorder. We also discuss the limitations and recommended future research directions of multi-omics studies on these diseases.

Dioxin-like molecules have been associated with endocrine disruption and liver disease. To better understand aryl hydrocarbon receptor (AHR) biology, metabolic phenotyping and liver proteomics were performed in mice following ligand-activation or whole-body genetic ablation of this receptor. Male wild type (WT) and Ahr -/- mice (Taconic) were fed a control diet and exposed to 3,3\',4,4\',5-pentachlorobiphenyl (PCB126) (61 nmol/kg by gavage) or vehicle for two weeks. PCB126 increased expression of canonical AHR targets (Cyp1a1 and Cyp1a2) in WT but not Ahr -/-. Knockouts had increased adiposity with decreased glucose tolerance; smaller livers with increased steatosis and perilipin-2; and paradoxically decreased blood lipids. PCB126 was associated with increased hepatic triglycerides in Ahr -/-. The liver proteome was impacted more so by Ahr -/- genotype than ligand-activation, but top gene ontology (GO) processes were similar. The PCB126-associated liver proteome was Ahr-dependent. Ahr principally regulated liver metabolism (e.g., lipids, xenobiotics, organic acids) and bioenergetics, but it also impacted liver endocrine response (e.g., the insulin receptor) and function, including the production of steroids, hepatokines, and pheromone binding proteins. These effects could have been indirectly mediated by interacting transcription factors or microRNAs. The biologic roles of the AHR and its ligands warrant more research in liver metabolic health and disease.

UNASSIGNED: Hepatocellular carcinoma (HCC) prediction models can inform clinical decisions about HCC screening provided their predictions are robust. We conducted an external validation of 6 HCC prediction models for UK patients with cirrhosis and a HCV virological cure.
UNASSIGNED: Patients with cirrhosis and cured HCV were identified from the Scotland HCV clinical database (N = 2,139) and the STratified medicine to Optimise Treatment of Hepatitis C Virus (STOP-HCV) study (N = 606). We calculated patient values for 4 competing non-genetic HCC prediction models, plus 2 genetic models (for the STOP-HCV cohort only). Follow-up began at the date of sustained virological response (SVR) achievement. HCC diagnoses were identified through linkage to nation-wide cancer, hospitalisation, and mortality registries. We compared discrimination and calibration measures between prediction models.
UNASSIGNED: Mean follow-up was 3.4-3.9 years, with 118 (Scotland) and 40 (STOP-HCV) incident HCCs observed. The age-male sex-ALBI-platelet count score (aMAP) model showed the best discrimination; for example, the Concordance index (C-index) in the Scottish cohort was 0.77 (95% CI 0.73-0.81). However, for all models, discrimination varied by cohort (being better for the Scottish cohort) and by age (being better for younger patients). In addition, genetic models performed better in patients with HCV genotype 3. The observed 3-year HCC risk was 3.3% (95% CI 2.6-4.2) and 5.1% (3.5-7.0%) in the Scottish and STOP-HCV cohorts, respectively. These were most closely matched by aMAP, in which the mean predicted 3-year risk was 3.6% and 5.0% in the Scottish and STOP-HCV cohorts, respectively.
UNASSIGNED: aMAP was the best-performing model in terms of both discrimination and calibration and, therefore, should be used as a benchmark for rival models to surpass. This study underlines the opportunity for \'real-world\' risk stratification in patients with cirrhosis and cured HCV. However, auxiliary research is needed to help translate an HCC risk prediction into an HCC-screening decision.
UNASSIGNED: Patients with cirrhosis and cured HCV are at high risk of developing liver cancer, although the risk varies substantially from one patient to the next. Risk calculator tools can alert clinicians to patients at high risk and thereby influence decision-making. In this study, we tested the performance of 6 risk calculators in more than 2,500 patients with cirrhosis and cured HCV. We show that some risk calculators are considerably better than others. Overall, we found that the \'aMAP\' calculator worked the best, but more work is needed to convert predictions into clinical decisions.

UNASSIGNED: Generally diagnosis of non-alcoholic fatty disease is made on imaging, however, mild steatosis is difficult to diagnose on imaging. Liver biopsy is the procedure of choice but is not carried out as it is an invasive procedure. We describe our experience of 157 liver biopsies in living liver donors with normal body mass index (BMI) <23 kg/M2 (lean).
UNASSIGNED: The study was conducted at a tertiary care center in north India. Data of lean living donors who underwent a liver biopsy before donation were analyzed. Data are presented as percentage, mean, or median (25-75 interquartile range).
UNASSIGNED: Of 718 donors who had a liver biopsy before donation, 157 (21.8%) donors were lean (BMI < 23 kg/M2). Seventy-eight percent of lean donors had no or only one metabolic risk factor. Fifty-three (33.7%) of lean donors had nonalcoholic fatty liver (NAFL) in liver biopsy. When donors with NAFL were compared to donors with normal histology, donors with NAFL had significantly higher aspartate transaminase (26.6 ± 7.5 versus 23.7 ± 5.4, p = 0.007), alanine transaminase (33.4 ± 11.7 versus 27.8 ± 10.7, p = 0.003), and gamma glutamyl transpeptidase [25 (16-40.5) versus 18 (14-23), p = 0.003]. Only triglycerides (TGs) were statistically different among metabolic factors in lean NAFL and normal histology groups, 97 (70-161) versus 86 (62.5-114.7), p = 0.043. A total of 30% donors in the lean NAFL group had TGs >150 mg/dl as compared with 12.5% in the normal histology group, p = 0.009. Other metabolic risk factors were not statistically different.
UNASSIGNED: One third of lean donors had NAFL. Among all metabolic risk factors, only higher TGs levels showed a significant association with NAFL.

Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed.

Non-alcoholic fatty liver disease (NAFLD) is an important cause of liver disease worldwide with prevalence ranging from 10% to 30% in various countries. It has become an important cause of unexplained rise in transaminases, cryptogenic cirrhosis, and cryptogenic hepatocellular carcinoma. Pathogenesis is related to obesity, insulin resistance, oxidative stress, lipotoxicity, and resultant inflammation in the liver progressing to fibrosis. Pharmacological treatment in patients with NAFLD is still evolving and the treatment of these patients rests upon lifestyle modification with diet and exercise being the cornerstones of therapy. While there are many similarities between patients with NAFLD from Asia and the West, there are certain features which make the patients with NAFLD from Asia stand apart. This review highlights the data on NAFLD from Asia comparing it with the data from the West.