UNASSIGNED: After pancreaticoduodenectomy, 20-40% of patients develop steatotic liver disease (SLD), and steatohepatitis can be a problem. Although patatin-like phospholipase domain-containing 3 protein (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) polymorphisms are involved in SLD and steatohepatitis development, whether this is the case after pancreaticoduodenectomy is unclear.
UNASSIGNED: Forty-three patients with pancreatic cancer who underwent pancreaticoduodenectomy at our hospital between April 1, 2018, and March 31, 2021, were included. We extracted DNA from noncancerous areas of residual specimens after pancreaticoduodenectomy and determined PNPLA3 and TM6SF2 gene polymorphisms using real-time polymerase chain reaction. SLD was defined as a liver with an attenuation value of ≤40 HU or a liver-to-spleen ratio of ≤0.9 on computed tomography. We defined high hepatic fibrosis indexes (HFI) instead of steatohepatitis as a Fibrosis-4 index of ≥2.67 or nonalcoholic fatty liver disease fibrosis score of ≥0.675 in patients with SLD. The cumulative incidence of SLD (P = 0.299) and high HFI (P = 0.987) after pancreaticoduodenectomy were not significantly different between the PNPLA3 homozygous and minor allele groups. The incidences of high HFI at 1 year after pancreaticoduodenectomy were 16.8% and 27.0% in the TM6SF2 major homozygous and minor allele groups, respectively, with a significant difference in the cumulative incidence (P = 0.046).
UNASSIGNED: The TM6SF2 minor allele may contribute to steatohepatitis development after pancreaticoduodenectomy.

Metabolic-associated fatty liver disease (MAFLD) and its potential impact on the severity of COVID-19 have gained significant attention during the pandemic. This review aimed to explore the genetic determinants associated with MAFLD, previously recognized as non-alcoholic fatty liver disease (NAFLD), and their potential influence on COVID-19 outcomes. Various genetic polymorphisms, including PNPLA3 (rs738409), GCKR (rs780094), TM6SF2 (rs58542926), and LYPLAL1 (rs12137855), have been investigated in relation to MAFLD susceptibility and progression. Genome-wide association studies and meta-analyses have revealed associations between these genetic variants and MAFLD risk, as well as their effects on lipid metabolism, glucose regulation, and liver function. Furthermore, emerging evidence suggests a possible connection between these MAFLD-associated polymorphisms and the severity of COVID-19. Studies exploring the association between indicated genetic variants and COVID-19 outcomes have shown conflicting results. Some studies observed a potential protective effect of certain variants against severe COVID-19, while others reported no significant associations. This review highlights the importance of understanding the genetic determinants of MAFLD and its potential implications for COVID-19 outcomes. Further research is needed to elucidate the precise mechanisms linking these genetic variants to disease severity and to develop gene profiling tools for the early prediction of COVID-19 outcomes. If confirmed as determinants of disease severity, these genetic polymorphisms could aid in the identification of high-risk individuals and in improving the management of COVID-19.

BACKGROUND: Patients with chronic hepatitis C virus (HCV) infections differ in their risk for metabolic disorders and chronic kidney disease (CKD). The aim of this study was to investigate the effect of metabolic disorders induced by genetic factors on CKD in HCV-infected patients.
METHODS: Patients with chronic non-genotype 3 HCV infection with or without CKD were examined. PNPLA3 and TM6SF2 variants were determined using high-throughput sequencing. The relationships of variants and different combinations with metabolic disorders were analyzed in CKD patients. Univariate and multivariate analyses were used to identify factors associated with CKD.
RESULTS: There were 1022 patients with chronic HCV infection, 226 with CKD and 796 without CKD. The CKD group had more severe metabolic disorders, and also had higher prevalences of liver steatosis, the PNPLA3 rs738409 non-CC genotype, and the TM6SF2 rs58542926 CC genotype (all P < 0.05). Relative to patients with the PNPLA3 rs738409 CC genotype, patients with the non-CC genotype had a significantly decreased eGFR and a greater prevalence of advanced CKD (CKD G4-5). Patients with the TM6SF2 rs58542926 CC genotype had a lower eGFR and a higher prevalence of CKD G4-5 than those with the non-CC genotype. Multivariable analysis indicated that multiple metabolic abnormalities, including liver steatosis and the PNPLA3 rs738409 C > G variant, increased the risk of CKD, but the TM6SF2 rs58542926 C > T variant decreased the risk of CKD.
CONCLUSIONS: Specific PNPLA3 rs738409 and TM6SF2 rs58542926 variants are independent risk factors for CKD in patients with chronic HCV infections and are associated with the severity of renal injury.

The epidemic prevalence of non-alcoholic fatty liver disease (NAFLD), despite extensive research in the field, underlines the importance of focusing on personalized therapeutic approaches. However, nutrigenetic effects on NAFLD are poorly investigated. To this end, we aimed to explore potential gene-dietary pattern interactions in a NAFLD case-control study. The disease was diagnosed with liver ultrasound and blood collection was performed after an overnight fast. Adherence to four a posteriori, data-driven, dietary patterns was used to investigate interactions with PNPLA3-rs738409, TM6SF2-rs58542926, MBOAT7-rs641738, and GCKR-rs738409 in disease and related traits. IBM SPSS Statistics/v21.0 and Plink/v1.07 were used for statistical analyses. The sample consisted of 351 Caucasian individuals. PNPLA3-rs738409 was positively associated with disease odds (OR = 1.575, p = 0.012) and GCKR-rs738409 with lnC-reactive protein (CRP) (beta = 0.098, p = 0.003) and Fatty Liver Index (FLI) levels (beta = 5.011, p = 0.007). The protective effect of a \"Prudent\" dietary pattern on serum triglyceride (TG) levels in this sample was significantly modified by TM6SF2-rs58542926 (pinteraction = 0.007). TM6SF2-rs58542926 carriers may not benefit from a diet rich in unsaturated fatty acids and carbohydrates in regard to TG levels, a commonly elevated feature in NAFLD patients.

OBJECTIVE: We aimed (i) evaluating the relationship between non-alcoholic fatty liver disease (NAFLD) and thyroid function tests, (ii) testing if the relationship between NAFLD and thyroid dysfunction could be driven by the obesity and the IR degree, and (iii) exploring the influence of the patatin-like phospholipase domain-containing protein-3 (PNPLA3) I148M and the transmembrane 6 superfamily member 2 (TM6SF2) E167K polymorphisms on the association between NAFLD and thyroid function in children.
METHODS: We examined 2275 children and adolescents with obesity. Subclinical hypothyroidism (SH) was defined by thyroid-stimulating hormone (TSH) > 4.2 μUI/ml with normal fT3 and fT4.
RESULTS: Children with NAFLD showed higher SH prevalence than those without NAFLD (15.7% Vs 7.4%;p = 0.001) and showed an adjusted odds ratio (aOR) to have SH of 1.68 (95% CI:1.01-2.80;p = 0.04) while patients with SH had an aOR to show NAFLD of 2.13(95% CI:1.22-3.73;p = 0.008). Patients having severe obesity and IR degree presented an aOR to show both NAFLD and SH of 3.61 (95% CI:1.78-7.33;p < 0.0001). Subjects with NAFLD carrying the TM6SF2 167 K allele had lower TSH levels than non-carriers (p = 0.03) and showed an aOR to have SH of 0.10 (95% CI: 0.01-0.79;p = 0.02). No differences were found in carriers of the PNPLA3 148 M allele. A general linear model for TSH variance showed a significant association of TSH with TM6SF2 genotypes only in the NAFLD group (p = 0.001).
CONCLUSIONS: Children with obesity and NAFLD presented increase risk of SH and vice versa likely due to the adverse effect of duration of obesity, obesity degree, and IR. The TM6SF2 E167K exerts a protective role against SH in children with obesity and NAFLD.

UNASSIGNED: Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. A non-synonymous single nucleotide polymorphism (SNP) of the transmembrane 6 superfamily member 2 (TM6SF2) gene is associated with non-alcoholic fatty liver disease. SNPs of the TM6SF2 gene play an important role in the pathogenesis of HCC in alcoholic cirrhosis, but there are limited data regarding other possible etiologies. We aimed to evaluate the role of the rs58542926 polymorphism in the development of HCC in Egyptian chronic liver disease (CLD) patients.
UNASSIGNED: A total of 120 participants, including 40 HCC patients, 40 CLD patients, and 40 healthy controls, were selected. Real-time polymerase chain reaction (RT-PCR) was used to detect the TM6SF2 rs58542926 polymorphism.
UNASSIGNED: There were no significant differences among the three studied groups regarding age (p = 0.06) and gender (p = 0.75). Frequencies of the CT, TT, CT + TT genotypes and the T allele were significantly higher in HCC patients than in the CLD and control groups (p < 0.001, p = 0.005, and p < 0.001, respectively). CLD patients with the CT genotype had a significantly increased risk of HCC development (OR = 4.67, 95% CI: 1.67-12.90). Patients with the TT genotype had a significantly increased risk of HCC (OR = 9.33, 95% CI: 1.72-50.61). Moreover, the T allele was correlated with an increased risk of HCC (OR = 5.44, 95% CI: 2.09-14.17) compared to the C allele.
UNASSIGNED: The TM6SF2 rs58542926 genotype is associated with an increased risk of HCC in the Egyptian population.

Genetic variants in transmembrane 6 superfamily member 2 (TM6SF2), such as E167K, are associated with atherosclerotic cardiovascular disease (ASCVD). Chronic inflammation and lipid-laden macrophage foam cell formation are the central pathogeneses in the development of atherosclerosis. This study was undertaken to illustrate the biological function of TM6SF2 in macrophages and its role during atherosclerosis development. We generated myeloid cell-specific Tm6sf2 knockout mice on ApoE-deficient background (LysM Cre+/Tm6sf2fl/fl/ApoE-/-, TM6 mKO) with littermate LysM Cre-/Tm6sf2fl/fl/ApoE-/- (Control) mice as controls. Mice were fed a Western diet for 12 weeks to induce atherosclerosis. Myeloid Tm6sf2 deficiency inhibited atherosclerosis and decreased foam cells in the plaques without changing the plasma lipid profile. RNA sequencing of bone marrow-derived macrophages (BMDMs) from TM6 mKO mice demonstrated the downregulation of genes associated with inflammation, cholesterol uptake, and endoplasmic reticulum (ER) stress. TM6SF2 was upregulated by oxidized low-density lipoprotein (oxLDL) in macrophages. Silencing TM6SF2 in THP-1-derived macrophages and Tm6sf2 deficiency in BMDMs reduced inflammatory responses and ER stress and attenuated cholesterol uptake and foam cell formation, while the overexpression of TM6SF2 showed opposite effects. In conclusion, myeloid TM6SF2 deficiency inhibits atherosclerosis development and is a potential therapeutic target for the treatment of atherogenesis.

Background and aims: Nonalcoholic fatty liver disease (NAFLD) is a common cause of liver damage in people living with HIV (PLWHIV). Several studies have investigated candidate genes for susceptibility to NAFLD and to steatohepatitis. PNPLA3, TM6SF2, and MBOAT7-TMC4 have been reported to be associated with elevated ALT levels and the histologic parameters of nonalcoholic steatohepatitis and severity of fibrosis. Our objective was to analyze the relationship between PNPLA3, TM6SF2, and MBOAT7-TMC4 and steatosis, steatohepatitis, and liver fibrosis in PLWHIV with NAFLD. Method: A cohort of PLWHIV with persistently elevated aminotransferase levels and suspected NAFLD who underwent liver biopsy and determination of genetic variants was assessed at two large centers in Spain. All participants included in the current study were genotyped for rs738409 (PNPLA3), rs58542926 (TM6SF2), and rs641738 (MBOAT7-TMC4). Results: The study population comprised PLWHIV who were on stable antiretroviral therapy [7.7% women; median age, 49.3 years (44-53.4)]. The median CD4 count was 829 (650-980), 60% had metabolic syndrome, and 18.5% were diabetic. The median BMI was 28.9 (25.5-30.8). Patients with liver steatosis (any grade) vs. nonsteatosis tended to harbor the PNPLA3 G allele variant [57.6% vs. 16.7% (p = 0.09)], but not TM6SF2 or MBOAT7-TMC4 variants. However, those with steatohepatitis vs. nonsteatohepatitis significantly more frequently had the PNPLA3 G allele variant [69.4% vs. 39.1% (p < 0.05)] and the MBOAT7-TMC4 A allele variant [75% vs. 42% (p < 0.05)]. In our cohort, the TM6SF2 gene variant was not associated with steatosis or steatohepatitis. The PNPLA3 G allele variant was associated with steatohepatitis [OR 4.9 (1.3-18); p 0.02] and liver fibrosis [OR 4.3 (1.1-17.4); p 0.04], and the MBOAT7-TMC4 A allele variant was associated with steatohepatitis [OR 6.6 (1.6-27.6); p 0.01]. Conclusion: The PNPLA3 G allele variant and MBOAT7-TMC4 A allele variant were associated with steatohepatitis and liver fibrosis in PLWHIV with persistently elevated aminotransferases and NAFLD. We recommend routine genotyping for PNPLA3 and MBOAT7-TMC4 in PLWHIV with NAFLD to identify those at higher risk of progression.

BACKGROUND: The lack of effective pharmacotherapies for nonalcoholic fatty liver disease (NAFLD) is mainly attributed to insufficient research on its pathogenesis. The pathogenesis of TM6SF2-efficient NAFLD remains unclear, resulting in a lack of therapeutic strategies for TM6SF2-deficient patients.
OBJECTIVE: To investigate the role of TM6SF2 in fatty acid metabolism in the context of fatty liver and propose possible therapeutic strategies for NAFLD caused by TM6SF2 deficiency.
METHODS: Liver samples collected from both NAFLD mouse models and human participants (80 cases) were used to evaluate the expression of TM6SF2 by using western blotting, immunohistochemistry, and quantitative polymerase chain reaction. RNA-seq data retrieved from the Gene Expression Omnibus database were used to confirm the over-expression of TM6SF2. Knockdown and overexpression of TM6SF2 were performed to clarify the mechanistic basis of hepatic lipid accumulation in NAFLD. MK-4074 administration was used as a therapeutic intervention to evaluate its effect on NAFLD caused by TM6SF2 deficiency.
RESULTS: Hepatic TM6SF2 levels were elevated in patients with NAFLD and NAFLD mouse models. TM6SF2 overexpression can reduce hepatic lipid accumulation, suggesting a protective role for TM6SF2 in a high-fat diet (HFD). Downregulation of TM6SF2, simulating the TM6SF2 E167K mutation condition, increases intracellular lipid deposition due to dysregulated fatty acid metabolism and is characterized by enhanced fatty acid uptake and synthesis, accompanied by impaired fatty acid oxidation. Owing to the potential effect of TM6SF2 deficiency on lipid metabolism, the application of an acetyl-CoA carboxylase inhibitor (MK-4074) could reverse the NAFLD phenotypes caused by TM6SF2 deficiency.
CONCLUSIONS: TM6SF2 plays a protective role in the HFD condition; its deficiency enhanced hepatic lipid accumulation through dysregulated fatty acid metabolism, and MK-4074 treatment could alleviate the NAFLD phenotypes caused by TM6SF2 deficiency.

Pancreatic and liver cancer are leading causes of cancer deaths, and by 2030, they are projected to become the second and the third deadliest cancer respectively. Cancer metabolism, especially lipid metabolism, plays an important role in progression and metastasis of many types of cancer, including pancreatic and liver cancer. Lipid droplets are intracellular organelles that store neutral lipids, but also act as molecular messengers, and signaling factors. It is becoming increasingly evident that alterations in the regulation of lipid droplets and their associated factors influence the risk of developing not only metabolic disease but also fibrosis and cancer. In the current review article, we summarized recent findings concerning the roles of lipid droplet-associated factors, patatin-like phospholipase domain-containing 3, Transmembrane 6 superfamily member 2, and 17β-hydroxysteroid dehydrogenase 11 and 13 as well as genetic variants in pancreatic and hepatic diseases. A better understanding of cancer type- and cell type-specific roles of lipid droplet-associated factors is important for establishing new therapeutic options in the future.