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Background and Aims: Crohn's disease (CD) confers an increased risk of nonalcoholic fatty liver disease (NAFLD), but the pathogenesis remains poorly understood. We determined if active intestinal inflammation increases the risk of NAFLD in patients with CD., Methods: Two cohorts (2017/2018 and 2020) with CD and no known liver disease were enrolled consecutively during staging magnetic resonance enterography. We quantified proton density fat fraction, MaRIA (Magnetic Resonance Index of Activity), and visceral adipose tissue. NAFLD was diagnosed when proton density fat fraction ≥5.5%. Synchronous endoscopy was graded by the Simple Endoscopic Score for CD and Rutgeerts score, while clinical activity was graded by the Harvey-Bradshaw index. Cytokine profiling was performed for the 2020 cohort. Transient elastography and liver biopsy were requested by standard of care., Results: NAFLD was diagnosed in 40% (n = 144 of 363), with higher prevalence during radiographically quiescent disease (odds ratio, 1.7; P = .01), independent of body mass index/visceral adipose tissue (adjusted odds ratio, 7.8; P = .03). These findings were corroborated by endoscopic disease activity, but not by aggregate clinical symptoms. Circulating interleukin-8 was independent of body mass index to predict NAFLD, but traditional proinflammatory cytokines were not. NAFLD subjects had similar liver stiffness estimates regardless of CD activity. Definitive or borderline steatohepatitis was present in most patients that underwent liver biopsy., Conclusions: Quiescent CD is associated with risk of NAFLD. These findings suggest potentially distinct pathogenic mechanisms of NAFLD in patients with CD compared with the prevailing leaky gut hypothesis proposed for individuals without inflammatory bowel disease. Future validation and mechanistic studies are needed to dissect these distinct disease modifying factors., (© The Author(s) 2023. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Genetic mutations causing defective VLDL secretion and low LDL cholesterol are associated with hepatic steatosis and nonalcoholic fatty liver disease (NAFLD)., Aims: Determine if low LDL cholesterol (< 5th percentile) was an independent predictor of hepatic steatosis., Methods: Secondary data analysis of the Dallas Heart study (an urban, multiethnic, probability-based sample), we defined hepatic steatosis utilizing intrahepatic triglyceride (IHTG) analyzed using magnetic resonance spectroscopy in conjunction and available demographic, serological and genetic information. We exclude patients on lipid lowering medications., Results: Of the 2094 subjects that met our exclusion criteria, 86 had a low LDL cholesterol, of whom 19 (22%) exhibited hepatic steatosis. After matching for age, sex, BMI, and alcohol consumption, low LDL cholesterol was not a risk factor for hepatic steatosis compared to those with normal (50-180 mg/dL) or high (> 180 mg/dL) LDL. When analyzed as a continuous variable, we observed lower IHTG in the low LDL group compared to the normal or high LDL groups (2.2%, 3.5%, 4.6%; all pairwise comparisons p < 0.001). Subjects with both hepatic steatosis and low LDL cholesterol exhibited a more favorable lipid profile but similar insulin resistance and hepatic fibrosis risk compared to other subjects with hepatic steatosis. The distribution of variant alleles associated with NAFLD, including PNPLA3, GCKR, and MTTP was indistinguishable between subjects with hepatic steatosis and low versus high LDL cholesterol., Conclusion: These findings suggest that low serum LDL levels are not a useful predictor of hepatic steatosis and NAFLD. Moreover, subjects with low LDL exhibit a more favorable lipid profile and lower IHTG., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Metabolic syndrome may contribute to the rising incidence of multiple gastrointestinal (GI) cancers in recent birth cohorts. However, other than hepatocellular carcinoma, the association between nonalcoholic fatty liver disease (NAFLD) and risk of non-liver GI cancers is unexplored. We prospectively examined the associations of NAFLD risk with GI cancers among 319,290 participants in the UK Biobank (2006-2019). Baseline risk for NAFLD was estimated using the Dallas Steatosis Index, a validated prediction tool. Multivariable Cox models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) according to NAFLD risk categories: low (<20%), intermediate (20%-49%), and high (≥50%). We also examined the associations by age of cancer diagnosis (earlier onset [<60] vs. ≥60). A total of 273 incident liver cancer and 4789 non-liver GI cancer cases were diagnosed. Compared with individuals at low risk for NAFLD, those at high risk had 2.41-fold risk of liver cancer (RR = 2.41, 95% CI: 1.73-3.35) and 23% increased risk of non-liver GI cancers (RR = 1.23, 95% CI: 1.14-1.32) (all p trend  < 0.001). Stronger associations were observed for men and individuals who were obese (all p interaction  < 0.05). NAFLD-associated elevated risk was stronger for earlier-onset cancers. For each 25% increase in NAFLD risk, the RRs for earlier-onset cancers were 1.32 (95% CI: 1.05-1.66) for esophageal cancer, 1.35 (95% CI: 1.06-1.72) for gastric cancer, 1.34 (95% CI: 1.09-1.65) for pancreatic cancer, and 1.10 (95% CI: 1.01-1.20) for colorectal cancer. Conclusion: NAFLD risk was associated with an increased risk of liver and most GI cancers, especially those of earlier onset., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Nonalcoholic fatty liver disease (NAFLD) is a global public health crisis that affects one quarter of the world population. 1 Preventing either cardiometabolic or liver-related complications by achieving weight loss and resolving hepatic steatosis would be the central goal of a NAFLD screening program in the primary care setting. Despite the overwhelming prevalence and the multimodal impact on health posed by NAFLD, specialty society guidelines do not recommend screening for NAFLD in the general population, 2 partly owing to the as-yet unproven cost benefit., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: We previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors., Approach and Results: We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impaired VLDL-triglyceride (TG) secretion, and one with normal VLDL-TG secretion. We identified three metabolic subtypes: A (47%), B (27%), and C (26%). Subtype A phenocopied the metabolome of mice with impaired VLDL-TG secretion; subtype C phenocopied the metabolome of mice with normal VLDL-TG; and subtype B showed an intermediate signature. The percent of patients with NASH and fibrosis was comparable among subtypes, although subtypes B and C exhibited higher liver enzymes. Serum VLDL-TG levels and secretion rate were lower among subtype A compared with subtypes B and C. Subtype A VLDL-TG and VLDL-apolipoprotein B concentrations were independent of steatosis, whereas subtypes B and C showed an association with these parameters. Serum TG, cholesterol, VLDL, small dense LDL 5,6 , and remnant lipoprotein cholesterol were lower among subtype A compared with subtypes B and C. The 10-year high risk of CVD, measured with the Framingham risk score, and the frequency of patatin-like phospholipase domain-containing protein 3 NAFLD risk allele were lower in subtype A., Conclusions: Metabolomic signatures identify three NAFLD subgroups, independent of histological disease severity. These signatures align with known CVD and genetic risk factors, with subtype A exhibiting a lower CVD risk profile. This may account for the variation in hepatic versus cardiovascular outcomes, offering clinically relevant risk stratification., (© 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background & Aims: Vacuole membrane protein 1 (VMP1) is an endoplasmic reticulum (ER) transmembrane protein that regulates the formation of autophagosomes and lipid droplets. Recent evidence suggests that VMP1 plays a critical role in lipoprotein secretion in zebra fish and cultured cells. However, the pathophysiological roles and mechanisms by which VMP1 regulates lipoprotein secretion and lipid accumulation in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are unknown., Methods: Liver-specific and hepatocyte-specific Vmp1 knockout mice as well as Vmp1 knock-in mice were generated by crossing Vmp1 flox or Vmp1 KI mice with albumin-Cre mice or by injecting AAV8-TBG-cre, respectively. Lipid and energy metabolism in these mice were characterized by metabolomic and transcriptome analyses. Mice with hepatic overexpression of VMP1 who were fed a NASH diet were also characterized., Results: Hepatocyte-specific deletion of Vmp1 severely impaired VLDL secretion resulting in massive hepatic steatosis, hepatocyte death, inflammation and fibrosis, which are hallmarks of NASH. Mechanistically, loss of Vmp1 led to decreased hepatic levels of phosphatidylcholine and phosphatidylethanolamine as well as to changes in phospholipid composition. Deletion of Vmp1 in mouse liver also led to the accumulation of neutral lipids in the ER bilayer and impaired mitochondrial beta-oxidation. Overexpression of VMP1 ameliorated steatosis in diet-induced NASH by improving VLDL secretion. Importantly, we also showed that decreased liver VMP1 is associated with NAFLD/NASH in humans., Conclusions: Our results provide novel insights on the role of VMP1 in regulating hepatic phospholipid synthesis and lipoprotein secretion in the pathogenesis of NAFLD/NASH., Lay Summary: Non-alcoholic fatty liver disease and its more severe form, non-alcoholic steatohepatitis, are associated with a build-up of fat in the liver (steatosis). However, the exact mechanisms that underly steatosis in patients are not completely understood. Herein, the authors identified that the lack of a protein called VMP1 impairs the secretion and metabolism of fats in the liver and could therefore contribute to the development and progression of non-alcoholic fatty liver disease., Competing Interests: Conflict of interest The authors who have taken part in this study declare that they have nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Human and animal model data show that maternal obesity promotes nonalcoholic fatty liver disease in offspring and alters bile acid (BA) homeostasis. Here we investigated whether offspring exposed to maternal obesogenic diets exhibited greater cholestatic injury. We fed female C57Bl6 mice conventional chow (CON) or high fat/high sucrose (HF/HS) diet and then bred them with lean males. Offspring were fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 2 weeks to induce cholestasis, and a subgroup was then fed CON for an additional 10 days. Additionally, to evaluate the role of the gut microbiome, we fed antibiotic-treated mice cecal contents from CON or HF/HS offspring, followed by DDC for 2 weeks. We found that HF/HS offspring fed DDC exhibited increased fine branching of the bile duct (ductular reaction) and fibrosis but did not differ in BA pool size or intrahepatic BA profile compared to offspring of mice fed CON. We also found that after 10 days recovery, HF/HS offspring exhibited sustained ductular reaction and periportal fibrosis, while lesions in CON offspring were resolved. In addition, cecal microbiome transplant from HF/HS offspring donors worsened ductular reaction, inflammation, and fibrosis in mice fed DDC. Finally, transfer of the microbiome from HF/HS offspring replicated the cholestatic liver injury phenotype. Taken together, we conclude that maternal HF/HS diet predisposes offspring to increased cholestatic injury after DDC feeding and delays recovery after returning to CON diets. These findings highlight the impact of maternal obesogenic diet on hepatobiliary injury and repair pathways during experimental cholestasis., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Regulating dietary fat absorption may impact progression of nonalcoholic fatty liver disease (NAFLD). Here, we asked if inducible inhibition of chylomicron assembly, as observed in intestine-specific microsomal triglyceride (TG) transfer protein knockout mice (Mttp-IKO), could retard NAFLD progression and/or reverse established fibrosis in two dietary models. Mttp-IKO mice fed a methionine/choline-deficient (MCD) diet exhibited reduced hepatic TGs, inflammation, and fibrosis, associated with reduced oxidative stress and downstream activation of c-Jun N-terminal kinase and nuclear factor kappa B signaling pathways. However, when Mttp flox mice were fed an MCD for 5 weeks and then administered tamoxifen to induce Mttp-IKO, hepatic TG was reduced, but inflammation and fibrosis were increased after 10 days of reversal along with adaptive changes in hepatic lipogenic mRNAs. Extending the reversal time, following 5 weeks of MCD feeding to 30 days led to sustained reductions in hepatic TG, but neither inflammation nor fibrosis was decreased, and both intestinal permeability and hepatic lipogenesis were increased. In a second model, similar reductions in hepatic TG were observed when mice were fed a high-fat/high-fructose/high-cholesterol (HFFC) diet for 10 weeks, then switched to chow ± tamoxifen (HFFC → chow) or (HFFC → Mttp-IKO chow), but again neither inflammation nor fibrosis was affected. In conclusion, we found that blocking chylomicron assembly attenuates MCD-induced NAFLD progression by reducing steatosis, oxidative stress, and inflammation. In contrast, blocking chylomicron assembly in the setting of established hepatic steatosis and fibrosis caused increased intestinal permeability and compensatory shifts in hepatic lipogenesis that mitigate resolution of inflammation and fibrogenic signaling despite 50-90-fold reductions in hepatic TG., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Crohn's disease (CD) patients have more than double the risk of nonalcoholic fatty liver disease (NAFLD) compared with the general population after considering traditional risk factors. NAFLD remains underappreciated because routine imaging and liver biochemistries are neither sensitive nor specific for the diagnosis. Here we developed a Clinical Prediction Tool for NAFLD in CD (CPN-CD) using readily accessible parameters to diagnose NAFLD, as determined by magnetic resonance proton density fat fraction (PDFF)., Methods: A total of 311 consecutive CD patients who underwent magnetic resonance enterography from June 1, 2017, to May 31, 2018, were screened for NAFLD, defined as a PDFF >5.5% after excluding other liver diagnoses. CPN-CD was derived using binary multivariate logistic regression and internally validated with a 10-fold cross-validation. CPN-CD was compared with the Hepatic Steatosis Index (HSI) by the C-statistic and categorical Net Reclassification Improvement (NRI)., Results: CPN-CD included age, sex, ethnicity/race, serum alanine aminotransferase, body mass index, known cardiometabolic diagnoses, CD duration, and current use of azathioprine/6-mercaptopurine. At <20% risk, NAFLD could be excluded with a sensitivity of 86% (negative predictive value, 86%). At ≥50% risk, NAFLD was diagnosed with a specificity of 87% (positive predictive value, 75%). CPN-CD exhibited good discrimination (C-statistic 0.85) compared with fair discrimination of the HSI (C-statistic, 0.76). CPN-CD was superior to the HSI by net reclassification improvement (+0.20; P < 0.001) and decision curve analysis., Conclusions: CPN-CD outperforms HSI in detecting NAFLD in patients with CD. Future directions include external validation, outcome validation, and testing generalizability to patients with ulcerative colitis., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background & Aims: Tools have been developed to determine risk for nonalcoholic fatty liver disease (NAFLD) based on imaging, which does not always detect early-grade hepatic steatosis. We aimed to develop a tool to identify patients with NAFLD using 1 H MR spectroscopy (MRS)., Methods: We collected data from the Dallas Heart Study-a multiethnic, population-based, probability study of adults (18-65 y) that comprised an in-home medical survey; collection of fasting blood samples; MRS images to measure cardiac mass/function, abdominal subcutaneous/visceral adiposity; and quantification of hepatic triglyceride concentration, from 2000 through 2009. NAFLD were defined as 5.5% or more liver fat and we excluded patients with more than moderate alcohol use; 737 patients were included in the final analysis. We performed binary multivariable logistic regression analysis to develop a tool to identify patients with NAFLD and evaluate interactions among variables. We performed an internal validation analysis using 10-fold cross validation., Results: We developed the Dallas Steatosis Index (DSI) to identify patients with NAFLD based on level of alanine aminotransferase, body mass index, age, sex, levels of triglycerides and glucose, diabetes, hypertension, and ethnicity. The DSI discriminated between patients with vs without NAFLD with a C-statistic of 0.824. The DSI outperformed 4 risk analysis tools, based on net reclassification improvement and decision curve analysis., Conclusions: We developed an index, called the DSI, which accurately identifies patients with NAFLD based on MRS data. The DSI requires external validation, but might be used in development NAFLD screening programs, in monitoring progression of hepatic steatosis, and in epidemiology studies., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning worldwide epidemic whose etiology reflects multiple interactions between environmental and genetic factors. Here, we review the major pathways and dominant genetic modifiers known to be relevant players in human NAFLD and which may determine key components of the heritability of distinctive disease traits including steatosis and fibrosis. In addition, we have employed general assumptions which are based on known genetic factors in NAFLD to build a systems biology prediction model that includes functional enrichment. This prediction model highlights additional complementary pathways that represent plausible intersecting signaling networks that we define here as an NAFLD-Reactome. We review the evidence connecting variants in each of the major known genetic modifiers (variants in patatin-like phospholipase domain containing 3, transmembrane 6 superfamily member 2, membrane-bound O-acyltransferase domain containing 7, glucokinase regulator, and hydroxysteroid 17-beta dehydrogenase 13) to NAFLD and expand the associated underlying mechanisms using functional enrichment predictions, based on both preclinical and cell-based experimental findings. These major candidate gene variants function in distinct pathways, including substrate delivery for de novo lipogenesis; mitochondrial energy use; lipid droplet assembly, lipolytic catabolism, and fatty acid compartmentalization; and very low-density lipoprotein assembly and secretion. The NAFLD-Reactome model expands these pathways and allows for hypothesis testing, as well as serving as a discovery platform for druggable targets across multiple pathways that promote NAFLD development and influence several progressive outcomes. In conclusion, we summarize the strengths and weaknesses of studies implicating selected variants in the pathophysiology of NAFLD and highlight opportunities for future clinical research and pharmacologic intervention, as well as the implications for clinical practice., (© 2020 by the American Association for the Study of Liver Diseases.)

Nonalcoholic fatty liver disease (NAFLD) commonly coexists with Crohn's disease (CD); however, it remains unclear if it is more prevalent than would be expected as ultrasound surveys of CD patients report a very wide range of prevalence (9%-40%). 1-3 To address this uncertainty, we performed a prospective, cross-sectional survey of NAFLD in CD patients by generating magnetic resonance proton density fat fraction (MR-PDFF) maps as compared with 2 control populations. MR-PDFF provides a quantitative, sensitive and specific (97% and 100%, respectively) radiographic surrogate for liver fat. 4 ., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Studies show maternal obesity is a risk factor for metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) in offspring. Here we evaluated potential mechanisms underlying these phenotypes. Female C57Bl6 mice were fed chow or an obesogenic high-fat/high-sucrose (HF/HS) diet with subsequent mating of F 1 and F 2 female offspring to lean males to develop F 2 and F 3 generations, respectively. Offspring were fed chow or fibrogenic (high transfat, cholesterol, fructose) diets, and histopathological, metabolic changes, and bile acid (BA) homeostasis was evaluated. Chow-fed F 1 offspring from maternal HF/HS lineages (HF/HS) developed periportal fibrosis and inflammation with aging, without differences in hepatic steatosis but increased BA pool size and shifts in BA composition. F 1 , but not F 2 or F 3 , offspring from HF/HS showed increased steatosis on a fibrogenic diet, yet inflammation and fibrosis were paradoxically decreased in F 1 offspring, a trend continued in F 2 and F 3 offspring. HF/HS feeding leads to increased periportal fibrosis and inflammation in chow-fed offspring without increased hepatic steatosis. By contrast, fibrogenic diet-fed F 1 offspring from HF/HS dams exhibited worse hepatic steatosis but decreased inflammation and fibrosis. These findings highlight complex adaptations in NAFLD phenotypes with maternal diet.