Deep metabolic phenotyping of humans with protein-altering variants in using a genome-first approach.

Background & Aim: An unbiased genome-first approach can expand the molecular understanding of specific genes in disease-agnostic biobanks for deeper phenotyping. represents a good candidate for this approach due to its known association with steatotic liver disease (SLD).

Methods: We screened participants with whole-exome sequences in the Penn Medicine Biobank (PMBB, n >40,000) and the UK Biobank (UKB, n >200,000) for protein-altering variants in and evaluated their association with liver phenotypes and clinical outcomes.

The common p.Ile291Val variant of ERLIN1 enhances TM6SF2 function and is associated with protection against MASLD.

Background: The ERLIN1 p.Ile291Val single-nucleotide polymorphism (rs2862954) is associated with protection from steatotic liver disease (SLD), but effects of this variant on metabolic phenotypes remain uncertain.

Methods: Metabolic phenotypes and outcomes associated with ERLIN1 p.

Lipid droplets in steatotic liver disease.

Purpose Of Review: This review aims to discuss the most recent evidence exploring the role of lipid droplets in steatotic liver disease (SLD). We highlight the breadth of mechanisms by which lipid droplets may contribute to the progression of SLD with a particular focus on the role of lipid droplets as inducers of mechanical stress within hepatocytes and genetic mutations in lipid droplet associated proteins. Finally, this review provides an update on clinical trials exploring the therapeutic potential and strategies targeting lipid droplets.

Markers of adipose tissue fibrogenesis associate with clinically significant liver fibrosis and are unchanged by synbiotic treatment in patients with NAFLD.

Background And Aims: Subcutaneous adipose tissue (SAT) dysfunction contributes to NAFLD pathogenesis and may be influenced by the gut microbiota. Whether transcript profiles of SAT are associated with liver fibrosis and are influenced by synbiotic treatment (that changes the gut microbiome) is unknown. We investigated: (a) whether the presence of clinically significant, ≥F2 liver fibrosis associated with adipose tissue (AT) dysfunction, differential gene expression in SAT, and/or a marker of tissue fibrosis (Composite collagen gene expression (CCGE)); and (b) whether synbiotic treatment modified markers of AT dysfunction and the SAT transcriptome.

Ceramide synthase 6 (CerS6) is upregulated in alcohol-associated liver disease and exhibits sex-based differences in the regulation of energy homeostasis and lipid droplet accumulation.

Objective: Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality worldwide. Current strategies to manage ALD focus largely on advanced stage disease, however, metabolic changes such as glucose intolerance are apparent at the earliest stage of alcoholic steatosis and increase the risk of disease progression. Ceramides impair insulin signaling and accumulate in ALD, and metabolic pathways involving ceramide synthase 6 (CerS6) are perturbed in ALD during hepatic steatosis.

Aspirin is associated with a reduced incidence of liver disease in men.

Background: The hepatoprotective effects of aspirin have been observed in individuals with viral hepatitis; however, its impact on the general population remains uncertain. Understanding the association between aspirin use and the development of liver diseases is crucial for optimizing preventive strategies.

Methods: We identified individuals with aspirin use in the UK Biobank and the Penn Medicine Biobank, as well as propensity-score-matched controls.

Large-scale identification of undiagnosed hepatic steatosis using natural language processing.

Background: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity in people with and without diabetes, but it is underdiagnosed, posing challenges for research and clinical management. Here, we determine if natural language processing (NLP) of data in the electronic health record (EHR) could identify undiagnosed patients with hepatic steatosis based on pathology and radiology reports.

Methods: A rule-based NLP algorithm was built using a Linguamatics literature text mining tool to search 2.

Omega-3 intake is associated with liver disease protection.

Background: Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease are among the most common liver diseases worldwide, and there are currently no Food and Drug Administration (FDA)-approved treatments. Recent studies have focused on lifestyle changes to prevent and treat NAFLD. Omega-3 supplementation is associated with improved outcomes in patients with chronic liver disease.

Association of Statin Use With Risk of Liver Disease, Hepatocellular Carcinoma, and Liver-Related Mortality.

Importance: Given the burden of chronic liver disease on the health care system, more information on the hepatoprotective association of statins in the general population is needed.

Objective: To examine whether regular statin use is associated with a reduction in liver disease, particularly hepatocellular carcinoma (HCC) and liver-related deaths, in the general population.

Design, Setting, And Participants: This cohort study used data from the UK Biobank (UKB) (individuals aged 37-73 years) collected from baseline (2006-2010) to the end of follow-up in May 2021, from the TriNetX cohort (individuals aged 18-90 years) enrolled from baseline (2011-2020) until end of follow-up in September 2022, and from the Penn Medicine Biobank (PMBB) (individuals aged 18-102 years) with ongoing enrollment starting in 2013 to the end of follow-up in December 2020.

A coding variant in the microsomal triglyceride transfer protein reduces both hepatic steatosis and plasma lipids.

Background: Genetic inactivation and pharmacologic inhibition of the microsomal triglyceride transfer protein (MTP; gene name MTTP) inhibits hepatic secretion of VLDL, thereby reducing serum lipids and apoB at the expense of increasing hepatic steatosis.

Aim: To examine the effects of missense variants in MTTP on hepatic and circulating lipids.

Methods: We analysed the association of MTTP missense variants with metabolic, hepatic and clinical phenotypes in the Penn Medicine Biobank (PMBB; n = 37,960) and the UKBiobank (UKB; n = 451,444).

Concomitant western diet and chronic-binge alcohol dysregulate hepatic metabolism.

Background And Aims: There is significant overlap between non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) with regards to risk factors and disease progression. However, the mechanism by which fatty liver disease arises from concomitant obesity and overconsumption of alcohol (syndrome of metabolic and alcohol-associated fatty liver disease; SMAFLD), is not fully understood.

Methods: Male C57BL6/J mice were fed chow diet (Chow) or high-fructose, high-fat, high-cholesterol diet (FFC) for 4 weeks, then administered either saline or ethanol (EtOH, 5% in drinking water) for another 12 weeks.

Dietary Vitamin E Intake Is Associated With a Reduced Risk of Developing Digestive Diseases and Nonalcoholic Fatty Liver Disease.

Introduction: Vitamin E supplementation is recommended for the treatment of nonalcoholic fatty liver disease (NAFLD) for nondiabetic patients, but its preventative effects are unclear.

Methods: We assessed dietary vitamin E intake with disease phenotypes and evaluated vitamin E levels with the development of NAFLD.

Results: Data from >210,000 participants demonstrate that increased dietary vitamin E associates with reduced rates of several gastrointestinal diseases and reduced overall mortality.

A new perspective on NAFLD: Focusing on lipid droplets.

Lipid droplets (LDs) are complex and metabolically active organelles. They are composed of a neutral lipid core surrounded by a monolayer of phospholipids and proteins. LD accumulation in hepatocytes is the distinctive characteristic of non-alcoholic fatty liver disease (NAFLD), which is a chronic, heterogeneous liver condition that can progress to liver fibrosis and hepatocellular carcinoma.

Growth differentiation factor-15 and the association between type 2 diabetes and liver fibrosis in NAFLD.

Background: Type 2 diabetes mellitus (T2DM) is a strong risk factor for liver fibrosis in non-alcoholic fatty liver disease (NAFLD). It remains uncertain why T2DM increases the risk of liver fibrosis. It has been suggested that growth differentiation factor-15 (GDF-15) concentrations increase the risk of liver fibrosis.

Factors independently associated with cardiorespiratory fitness in patients with non-alcoholic fatty liver disease.

Unlabelled: Low cardiorespiratory fitness (CRF) is associated with non-alcoholic fatty liver disease (NAFLD) and low CRF is an important risk factor for cardiovascular disease. The factors that influence CRF in NAFLD are poorly understood and it has been suggested that reduced hepatic mitochondrial function (HMF) may be linked to low CRF. Therefore, our aim was to determine the factors associated with CRF in NAFLD.

Liver-specific ceramide reduction alleviates steatosis and insulin resistance in alcohol-fed mice.

Alcohol's impairment of both hepatic lipid metabolism and insulin resistance (IR) are key drivers of alcoholic steatosis, the initial stage of alcoholic liver disease (ALD). Pharmacologic reduction of lipotoxic ceramide prevents alcoholic steatosis and glucose intolerance in mice, but potential off-target effects limit its strategic utility. Here, we employed a hepatic-specific acid ceramidase (ASAH) overexpression model to reduce hepatic ceramides in a Lieber-DeCarli model of experimental alcoholic steatosis.

Complications, morbidity and mortality of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is an increasingly recognized public health problem, affecting up to a quarter of the world's adult population. The burden of NAFLD is influenced by the epidemics of obesity and type 2 diabetes mellitus (T2DM) and the prevalence of these conditions is not expected to decrease in the forthcoming decades. Consequently, the burden of NAFLD-related liver complications (non-alcoholic steatohepatitis [NASH], cirrhosis and hepatocellular carcinoma) and the need for life-saving liver transplantation are also expected to increase further in the near future.

Synbiotics Alter Fecal Microbiomes, But Not Liver Fat or Fibrosis, in a Randomized Trial of Patients With Nonalcoholic Fatty Liver Disease.

Background & Aims: Dysbiosis of the intestinal microbiota has been associated with nonalcoholic fatty liver disease (NAFLD). We investigated whether administration of a synbiotic combination of probiotic and prebiotic agents affected liver fat content, biomarkers of liver fibrosis, and the composition of the fecal microbiome in patients with NAFLD.

Methods: We performed a double-blind phase 2 trial of 104 patients with NAFLD in the United Kingdom.

In vitro effects of Bifidobacterium lactis-based synbiotics on human faecal bacteria.

Synbiotic supplements contain pre- and probiotics and are used to modulate gut microbiota composition. This study aimed to investigate effects of two synbiotic mixtures on human faecal bacteria in vitro. Short chain fructooligosaccharides (FOS) (1% w/v) combined with either Bifidobacterium lactis Bb12 or Bifidobacterium lactis HN019 (10 colony-forming units (CFU)/mL)] were added to pH-controlled anaerobic batch cultures inoculated with human faeces.

Efficacy and safety of anti-hyperglycaemic drugs in patients with non-alcoholic fatty liver disease with or without diabetes: An updated systematic review of randomized controlled trials.

Aim: There are no approved drugs for the treatment of non-alcoholic fatty liver disease (NAFLD). However, many randomized controlled trials (RCT) have examined the effect of anti-hyperglycaemic agents on NAFLD in patients with and without type 2 diabetes mellitus (T2DM), since both T2DM and insulin resistance are closely linked to this burdensome liver disease.

Methods: We systematically searched publication databases using predefined keywords to identify head-to-head or placebo-controlled RCTs (published until September 30, 2019) of NAFLD individuals testing the efficacy of anti-hyperglycaemic drugs to specifically treat NAFLD or non-alcoholic steatohepatitis (NASH).