Based on an in-depth understanding of diabetes heterogeneity, five novel subtypes of adult-onset diabetes have been identified. This study investigates the differential impact of metabolic dysfunction-associated fatty liver disease (MAFLD) on these subtypes using a Mendelian randomization (MR) approach, while also exploring modifiable mediating factors.

Genetic variants associated with MAFLD were selected at the genome-wide significance threshold (P < 5 × 10-8), with 16 variants used to assess causal associations with the risk of severe autoimmune diabetes (SAID), mild obesity-related diabetes (MOD), severe insulin-resistant diabetes (SIRD), severe insulin-deficient diabetes (SIDD), and mild age-related diabetes (MARD). Two-step MR was used to estimate total, direct, and mediated effects, analyzing 55 potential mediators across five domains. The primary method used was inverse variance weighting (IVW) along with a series of sensitivity analyses to ensure robustness of the results. Genetically predicted MAFLD was significantly associated with increased risk of MARD (OR = 1.171, 95 % CI 1.091-1.256), SIDD (OR = 1.158, 95 % CI 1.056-1.270), and SIRD (OR = 1.267, 95 % CI 1.119-1.434), with suggestive evidence for SAID (OR = 1.161, 95 % CI 1.016-1.327), but no association with MOD. Among all subtypes, waist-to-hip ratio adjusted for BMI (WHRadjBMI) was a common mediator, with liver fat, alanine aminotransferase (ALT), gamma-glutamyl transferase, fasting insulin (FI), and BMI mediating at least three subtypes. Liver fat accounted for the largest proportion of mediation (43.63 %-73.09 %), followed by ALT (8.99 %-17.93 %) and FI (6.81 %-13.04 %).

This study underscores the causal relationship between MAFLD and specific diabetes subtypes, highlighting the importance of integrated management of liver lipid metabolism, abdominal obesity, and blood glucose regulation. These findings support personalized intervention strategies.

There is a substantial heritable component to metabolic dysfunction-associated steatotic liver disease (MASLD), and several genetic variants that promote MASLD development or associate with its severity have been reported. These associations vary in terms of their effect size and degree of replication.

We developed a framework to classify previously identified MASLD genetic polymorphisms into 4 tiers based on effect size and extent of replication in the literature. We tested the association between "tier 1" single-nucleotide polymorphisms (OR ≥1.5, replicated in >2 independent studies) and biopsy measures of MASLD severity in a large, well-characterized histologic cohort of MASLD patients (n=3094).

Across 19 "tier 1" variants reflecting 11 genetic loci, only those in the PNPLA3-SAMM50-PARVB locus showed significant associations with biopsy-proven fibrosis severity and NAFLD activity score; the highest risk was for the rs738409 p.I148M variant in PNPLA3. A genetic risk score based on "tier 1" variants, as well as a previously developed genetic risk score based on variants in PNPLA3, TM6SF2, and HSD17B13, were both associated with fibrosis and NAFLD activity score, but these results were driven entirely by PNPLA3 rs738409.

Our study provides a framework to prioritize evaluation of genetic polymorphisms for future replication efforts and demonstrates that in a large case-only cohort, histologic severity of MASLD is only robustly associated with the presence of variation in PNPLA3 among known candidate genes. These findings may have implications for patient risk stratification based on the presence of PNPLA3 rs738409.

Ischemic cardiomyopathy (ICM) is associated with high mortality and hospitalization rates, and current treatments are suboptimal. The aim of this research was to identify novel therapeutic targets for ICM. The datasets GSE57338 and GSE5406 were obtained from the Gene Expression Omnibus (GEO) database. Gene modules were constructed using weighted gene co-expression network analysis (WGCNA), and the three relevant modules associated with ICM were identified. The biological functions and signaling pathways of the genes in these modules were further explored through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Protein-protein interaction (PPI) networks were employed to identify hub genes within these modules. Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression was performed to establish gene models, and 16 genes associated with left ventricular ejection fraction (LVEF) in ICM were identified. The genes were validated in heart tissues from human using quantitative real-time polymerase chain reaction (qRT-PCR). Among them, growth factor receptor-bound protein 14 (GRB14), ubiquitin C-terminal hydrolase L1 (UCHL1), and synuclein alpha (SNCA) were identified as key genes significantly associated with ICM. Additionally, key genes correlated with immune and stromal cell-related types were screened using xCell. In vivo and in vitro experiments demonstrated that inhibiting SNCA could improve cardiac dysfunction, inflammatory infiltration, and fibrosis in ICM. In conclusion, this study identified 16 genes closely related to LVEF and revealed that SNCA was a key gene in ICM, providing potential biomarkers and therapeutic targets for ICM.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rising globally. Recent studies have suggested connections between exposure to endocrine disrupting chemicals (EDCs) and the development of MASLD. Phthalates, which are commonly utilized as plasticizers, in building materials and consumer items, exhibit endocrine disrupting effects and have been shown to interfere with lipid metabolism in mechanistic studies. The objective of this systematic review was to examine the association between MASLD and exposure to phthalates in the adult human populations. We searched PubMed, Scopus and Web of Science for studies published from the inception of each database until December 12, 2024. The literature search yielded 10 cross-sectional studies, which were analyzed in detail. The key findings of this study indicate a potential correlation between the prevalence of MASLD and exposure to certain phthalates. Among the phthalates examined, the metabolites of bis(2-ethylhexyl) phthalate (DEHP) - namely MECPP, MEHHP, and MEOHP, demonstrated the strongest and most frequent associations with MASLD. All the current studies followed cross-sectional study designs, which limits the possibility to establish a causal relationship between MASLD and phthalate exposure. Therefore, longitudinal studies are needed to corroborate these findings and shed light on the involvement of phthalate exposure in MASLD.

Most forms of obesity are associated with chronic diseases that remain a global public health challenge.

Despite significant advancements in understanding its pathophysiology, effective management of obesity is hindered by the persistence of knowledge gaps in epidemiology, phenotypic heterogeneity and policy implementation.

This consensus statement by the European Society for Clinical Investigation identifies eight critical areas requiring urgent attention. Key gaps include insufficient long-term data on obesity trends, the inadequacy of body mass index (BMI) as a sole diagnostic measure, and insufficient recognition of phenotypic diversity in obesity-related cardiometabolic risks. Moreover, the socio-economic drivers of obesity and its transition across phenotypes remain poorly understood.

The syndemic nature of obesity, exacerbated by globalization and environmental changes, necessitates a holistic approach integrating global frameworks and community-level interventions. This statement advocates for leveraging emerging technologies, such as artificial intelligence, to refine predictive models and address phenotypic variability. It underscores the importance of collaborative efforts among scientists, policymakers, and stakeholders to create tailored interventions and enduring policies.

The consensus highlights the need for harmonizing anthropometric and biochemical markers, fostering inclusive public health narratives and combating stigma associated with obesity. By addressing these gaps, this initiative aims to advance research, improve prevention strategies and optimize care delivery for people living with obesity.

This collaborative effort marks a decisive step towards mitigating the obesity epidemic and its profound impact on global health systems. Ultimately, obesity should be considered as being largely the consequence of a socio-economic model not compatible with optimal human health.

Background: Biological aging is considered a vital risk factor for age-related diseases, but its role in non-alcoholic fatty liver disease (NAFLD) remains uncertain. This study aimed to evaluate the associations of biological aging with NAFLD and the modified effect of genetic susceptibility. Methods: This study included 329,040 participants from the UK Biobank and 6783 participants from the Dongfeng-Tongji Cohort in China. We calculated the chronological age-adjusted biological age as a surrogate measure for biological aging. Accelerated aging was defined as biological age that exceeded chronological age. The association between biological aging and the risk of NAFLD was assessed in the two cohorts. Polygenic risk scores (PRSs) were used to determine genetic susceptibility for NAFLD in the UK Biobank and further analyze the interaction with biological aging. Results: In the UK Biobank, one year older in age-adjusted biological age increased prevalent NAFLD risk by 6%. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) of NAFLD by accelerated aging were 1.35 (1.17, 1.56) and 1.69 (1.54, 1.85) compared to non-aging. In the Dongfeng-Tongji Cohort, biological aging was prospectively associated with NAFLD (accelerated aging: odds ratio (OR) (95% CI) = 1.18 (1.03, 1.36)). In the UK Biobank, high genetic risk was significantly associated with higher NAFLD risk compared to low genetic risk (HRs (95% CIs) = 1.65 (1.40, 1.95)). Analyses of joint effects showed that participants with high PRS and accelerated aging had the highest risk of NAFLD [2.66 (2.98, 3.57) and 2.06 (2.36, 3.96)]. However, biological aging was prospectively associated with NAFLD among participants regardless of genetic risk. There was no significant interaction between genetic risk and biological aging. Conclusions: Accelerated biological aging was associated with a higher risk of NAFLD independent of genetic susceptibility. Identifying populations with accelerated biological aging by the use of surrogate measures and timely intervention may be beneficial for the prevention of NAFLD.

Metabolic dysfunction-associated steatohepatitis (MASH) represents a progressive form of steatotic liver disease which increases the risk for fibrosis and advanced liver disease. The accumulation of discrete species of bioactive lipids has been postulated to activate signaling pathways that promote inflammation and fibrosis. However, the key pathogenic lipid species is a matter of debate. We explored candidates using various dietary, molecular, and genetic models. Mice fed a choline-deficient L-amino acid-defined high-fat diet (CDAHFD) developed steatohepatitis and manifested early markers of liver fibrosis associated with increased cholesterol content in liver lipid droplets within 5 d without any changes in total liver cholesterol content. Treating mice with antisense oligonucleotides against Coenzyme A synthase (Coasy) or treatment with bempedoic acid or atorvastatin decreased liver lipid droplet cholesterol content and prevented CDAHFD-induced MASH and the fibrotic response. All these salutary effects were abrogated with dietary cholesterol supplementation. Analysis of human liver samples demonstrated that cholesterol in liver lipid droplets was increased in humans with MASH and liver fibrosis and was higher in PNPLA3 I148M (variants rs738409) than in HSD17B13 variants (rs72613567). Together, these data identify cholesterol in liver lipid droplets as a critical mediator of MASH and demonstrate that Coenzyme A synthase knockdown and bempedoic acid are therapeutic approaches to reduce liver lipid droplet cholesterol content and thereby prevent the development of MASH and liver fibrosis.

Limited data have prevented routine genetic testing from being integrated into clinical practice in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to quantify the effect of genetic variants on changes in fibrosis severity per decade in MASLD.

This cross-sectional study included prospectively recruited adults with MASLD aged 18-70 who underwent magnetic resonance elastography (MRE) and genotyping for PNPLA3, TM6SF2, MBOAT7, GCKR, and HSD17B13. A genetic risk score (GRS) was calculated as the sum of established risk alleles in PNPLA3 minus protective variants in HSD17B13 (0=low risk, 1=high risk). We also estimated the polygenic risk score-hepatic fat content (PRS-HFC) and the adjusted version (PRS-5). The primary endpoint was the age-related change in liver stiffness measurement (LSM) on MRE by GRS. Findings were validated using an external cohort from Latin America.

Among 570 participants, the median age was 57 [49-64] years, 56.8% were women, and 34.2% were Hispanic. Median MRE was 2.4 [2.1-3.0] kPa, and 51% had high GRS. High GRS was independently associated with increased LSM (β=0.28 kPa, 95%CI:0.12-0.44, p=0.001) per 10-year age increase, while the low GRS group showed no significant difference. Similar findings were observed using PRS-HFC and PRS-5. PNPLA3 genotype alone also predicted higher LSM (C/G: β=0.32 kPa, 95%CI:0.02-0.61, p=0.034; G/G: β=0.87 kPa, 95%CI:0.52-1.22, p<0.0001) and G/G genotype was associated with significantly higher LSM by age 44, which was consistent in the validation population.

GRS, PRS-HFC, PRS-5, and PNPLA3 genotypes alone are associated with greater fibrosis per decade, resulting in divergent disease trajectories starting in midlife. Assessing genetic risk in MASLD will identify high-risk patients who require more frequent monitoring.

This study provides granular evidence that genetic predisposition, particularly the PNPLA3 G/G genotype, significantly influences the trajectory of liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), with a more pronounced impact emerging after the fourth decade of life. These findings highlight the importance of incorporating genetic risk assessment into MASLD management, as it allows for the early identification of high-risk individuals who may benefit from more frequent monitoring and targeted interventions. Given the rising global burden of MASLD, clinicians, researchers, and policymakers should consider integrating genetic stratification into existing risk assessment frameworks to refine screening and surveillance strategies. By optimizing patient selection for non-invasive fibrosis assessment and potential therapeutic interventions, this approach could enhance precision medicine efforts and may improve long-term outcomes.

The New England Bladder Cancer Study has recently reported an increased bladder cancer risk with occupational exposure to mononuclear aromatic organic solvents, including exposure to benzene, toluene, and xylene and their combination BTX. However, the mechanisms by which BTX influence bladder cancer are unclear. In this study, we evaluated the interaction between BTX and genetic markers in known bladder cancer susceptibility loci and in variants shown to impact the metabolism of these solvents. We used multivariate logistic regression to calculate the ORs, 95% confidence intervals, and P values for multiplicative interaction in 1,182 cases and 1,408 controls from a population-based case-control study from New England. Lifetime occupational exposure to benzene, toluene, xylene, and BTX were assessed using occupational histories and exposure-oriented modules in conjunction with a job-exposure matrix. Buccal cells from mouthwash samples were used to conduct genotyping. Subjects with the highest cumulative exposure to benzene and who carried a risk allele in rs72826305 (CASC15) had an increased risk of bladder cancer (OR = 2.56, 95% confidence interval, 1.28-5.12) compared with those never exposed with no risk alleles (P interaction = 0.03). Additional suggestive joint effects with benzene were evident for those carrying genetic risk variants in FGFR3 (P value = 0.01) and GSTT1 (P interaction = 0.007). Bladder cancer risk is higher among those exposed to BTX-containing solvents who also harbor common variants in CASC15, FGFR3, and GSTT1, adding to the evidence of a plausible link between these exposures and bladder cancer risk. Prevention Relevance: Our findings suggest that bladder cancer risk is higher among those exposed to BTX-containing solvents who also harbor common genetic polymorphisms associated with bladder cancer. The joint contribution of genetics and occupational exposures may play an important role in the etiology of bladder cancer.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as the leading cause of chronic liver disease worldwide, reflecting the global epidemics of obesity, metabolic syndrome, and type 2 diabetes. Beyond its strong association with excess adiposity, MASLD encompasses a heterogeneous population that includes individuals with normal body weight ("lean MASLD") highlighting the complexity of its pathogenesis. This disease results from a complex interplay between genetic susceptibility, epigenetic modifications, and environmental factors, which converge to disrupt metabolic homeostasis. Adipose tissue dysfunction and insulin resistance trigger an overflow of lipids to the liver, leading to mitochondrial dysfunction, oxidative stress, and hepatocellular injury. These processes promote hepatic inflammation and fibrogenesis, driven by cross talk among hepatocytes, immune cells, and hepatic stellate cells, with key contributions from gut-liver axis perturbations. Recent advances have unraveled pivotal molecular pathways, such as transforming growth factor-β signaling, Notch-induced osteopontin, and sphingosine kinase 1-mediated responses, that orchestrate fibrogenic activation. Understanding these interconnected mechanisms is crucial for developing targeted therapies. This review integrates current knowledge on the pathophysiology of MASLD, emphasizing emerging concepts such as lean metabolic dysfunction-associated steatohepatitis (MASH), epigenetic alterations, hepatic extracellular vesicles, and the relevance of extrahepatic signals. It also discusses novel therapeutic strategies under investigation, aiming to provide a comprehensive and structured overview of the evolving MASLD landscape for both basic scientists and clinicians.

Radiotherapy-induced hearing impairment significantly affects patients' quality of life, yet its genetic basis remains poorly understood. This study seeks to identify genetic variants associated with radiotherapy-induced tinnitus and hearing loss and explore their functional implications. A genome-wide association study (GWAS) was conducted to identify single-nucleotide polymorphisms (SNPs) associated with radiotherapy-induced tinnitus and hearing loss. Protein-protein interaction networks and functional enrichment analyses were performed to explore underlying biological pathways. A phenome-wide association study (PheWAS) analysis across five databases examined associations between identified SNPs and various phenotypes. The GWAS identified 97 SNPs significantly associated with radiotherapy-induced tinnitus and 76 SNPs with hearing loss. Tinnitus-associated variants were enriched in pathways involving Wnt signaling and telomerase RNA regulation, while hearing-loss-associated variants were linked to calcium-dependent cell adhesion and neurotransmitter receptor regulation. The PheWAS analysis revealed significant associations between these hearing-impairment-related SNPs and metabolic phenotypes, particularly BMI and metabolic disorders. A chromosomal distribution analysis showed concentrated significant SNPs on chromosomes 1, 2, 5, and 10. This study identified distinct genetic architectures underlying radiotherapy-induced tinnitus and hearing loss, revealing different molecular pathways involved in their pathogenesis. The unexpected association with metabolic phenotypes suggests potential interactions between metabolic status and susceptibility to radiotherapy-induced hearing complications. These findings provide insights for developing genetic screening tools and targeted interventions to prevent or mitigate radiotherapy-related hearing damage.

Advances in nucleic acid delivery have positioned the liver as a key target for gene therapy, with adeno-associated virus vectors showing long-term effectiveness in treating hemophilia. Steatotic liver disease (SLD), the most common liver condition globally, primarily results from metabolic dysfunction-associated and alcohol-associated liver diseases. In some individuals, SLD progresses from simple steatosis to steatohepatitis, cirrhosis, and eventually hepatocellular carcinoma, driven by a complex interplay of genetic, metabolic, and environmental factors. Genetic variations in various lipid metabolism-related genes, such as patatin-like phospholipase domain-containing protein 3 (PNPLA3), 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13), and mitochondrial amidoxime-reducing component 1 (MTARC1), impact the progression of SLD and offer promising therapeutic targets. This review largely focuses on genes identified through clinical association studies, as they are more likely to be effective and safe for therapeutic intervention. While preclinical research continues to deepen our understanding of genetic factors, early-stage clinical trials involving gene-based SLD therapies, including transient antisense and small-molecule approaches, are helping prioritize therapeutic targets. Meanwhile, hepatocyte gene editing technologies are advancing rapidly, offering alternatives to transient methods. As such, gene-based therapies show significant potential for preventing the progression of SLD and enhancing long-term liver health.

Genome-wide association studies have linked millions of genetic variants to biomedical phenotypes, but their utility has been limited by lack of mechanistic understanding and widespread epistatic interactions. Recently, Transformer models have emerged as a powerful machine learning architecture with potential to address these and other challenges. Accordingly, here we introduce the Genotype-to-Phenotype Transformer (G2PT), a framework for modeling hierarchical information flow among variants, genes, multigenic systems, and phenotypes. As proof-of-concept, we use G2PT to model the genetics of TG/HDL (triglycerides to high-density lipoprotein cholesterol), an indicator of metabolic health. G2PT predicts this trait via attention to 1,395 variants underlying at least 20 systems, including immune response and cholesterol transport, with accuracy exceeding state-of-the-art. It implicates 40 epistatic interactions, including epistasis between APOA4 and CETP in phospholipid transfer, a target pathway for cholesterol modification. This work positions hierarchical graph transformers as a next-generation approach to polygenic risk.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), has become a pressing global health concern. The complexity of MASLD and the lack of universally effective treatments expose the limitations of current interventions, which focus mainly on lifestyle modifications. Here, we explore the multilayered nature of MASLD, emphasizing its pathophysiology in shaping future medical and lifestyle interventions from a personalized medicine perspective, based on individual molecular profiles. Additionally, we address the limitations of current animal models in reflecting human metabolic syndrome and sex-specific differences. We argue that a holistic approach, integrating social determinants of health, patient preferences, and adherence patterns, is essential for advancing MASLD management effectively.

East Asian populations, which account for approximately 20% of the global population, have become central to the worldwide rise of metabolic diseases over the past few decades. The prevalence of metabolic disorders, including type 2 diabetes mellitus, hypertension and metabolic dysfunction-associated steatotic liver disease, has escalated sharply, contributing to a substantial burden of complications such as cardiovascular disease, chronic kidney disease, cancer and increased mortality. This concerning trend is primarily driven by a combination of genetic predisposition, unique fat distribution patterns and rapidly changing lifestyle factors, including urbanization and the adoption of Westernized dietary habits. Current advances in genomics, proteomics, metabolomics and microbiome research have provided new insights into the biological mechanisms that might contribute to the heightened susceptibility of East Asian populations to metabolic diseases. This Review synthesizes epidemiological data, risk factors and biomarkers to provide an overview of how metabolic diseases are reshaping public health in East Asia and offers insights into biological and societal drivers to guide effective, region-specific strategies.

Metabolic syndrome (MetS) and metabolic dysfunction-associated steatotic liver disease (MASLD) are closely related, with rapidly increasing prevalence globally, driving significant public health concerns. Both conditions share common pathophysiological mechanisms such as insulin resistance (IR), adipose tissue dysfunction, oxidative stress, and gut microbiota dysbiosis, which contribute to their co-occurrence and progression. While the clinical implications of this overlap, including increased cardiovascular, renal, and hepatic risk, are well recognized, current diagnostic and therapeutic approaches remain insufficient due to the clinical and individuals' heterogeneity and complexity of these diseases. This review aims to provide an in-depth exploration of the molecular mechanisms linking MetS and MASLD, identify critical gaps in our understanding, and highlight existing challenges in early detection and treatment. Despite advancements in biomarkers and therapeutic interventions, the need for a comprehensive, integrated approach remains. The review also discusses emerging therapies targeting specific pathways, the potential of precision medicine, and the growing role of artificial intelligence in enhancing research and clinical management. Future research is urgently needed to combine multi-omics data, precision medicine, and novel biomarkers to better understand the complex interactions between MetS and MASLD. Collaborative, multidisciplinary efforts are essential to develop more effective diagnostic tools and therapies to address these diseases on a global scale.

Steatotic liver disease (SLD) is influenced by both genetics and lifestyle factors, with lifestyle effects varying by genetic susceptibility. We aimed to evaluate gene-lifestyle interactions on SLD risk.

We included 28,215 UK Biobank participants with available data. Predictors were healthy lifestyle patterns, PNPLA3-rs738409, TM6SF2-rs58542926, a 16-variant hepatic steatosis polygenic risk score (PRS), and gene-environment interactions. Primary outcome was liver fat content (LFC); secondary outcomes were cT1 (a measure of liver inflammation/fibrosis) and SLD-related events.

Lifestyle predictors, except smoking, reduced LFC, while genetic predictors increased it. Genetic predictors significantly interacted with healthy lifestyle patterns, sedentary behavior and social connection. Lifestyle effects on lower LFC were up to 6.3-fold stronger in PNPLA3-rs738409-GG vs. -CC individuals, and 1.5-7.0 times higher in the top vs. bottom PRS quartile. PRS and PNPLA3 also interacted with alcohol consumption, diet, and PNPLA3 further interacted with physical activity. These interactions were more pronounced in overweight participants. Genetic factors and physical activity interacted to influence cT1, while PRS, PNPLA3 and sleep duration were associated with cardiovascular events.

Lifestyle effects on LFC, cT1 and cardiovascular events were accentuated in individuals at higher SLD genetic risk, implying lifestyle interventions may be more impactful in these populations.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by increased hepatic steatosis with cardiometabolic disease and is a leading cause of advanced liver disease. We review here the genetic basis of MASLD. The genetic variants most consistently associated with hepatic steatosis implicate genes involved in lipoprotein input or output, glucose metabolism, adiposity/fat distribution, insulin resistance, or mitochondrial/ER biology. The distinct mechanisms by which these variants promote hepatic steatosis result in distinct effects on cardiometabolic disease that may be best suited to precision medicine. Recent work on gene-environment interactions has shown that genetic risk is not fixed and may be exacerbated or attenuated by modifiable (diet, exercise, alcohol intake) and nonmodifiable environmental risk factors. Some steatosis-associated variants, notably those in patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), are associated with risk of developing adverse liver-related outcomes and provide information beyond clinical risk stratification tools, especially in individuals at intermediate to high risk for disease. Future work to better characterize disease heterogeneity by combining genetics with clinical risk factors to holistically predict risk and develop therapies based on genetic risk is required.

Alcohol-associated hepatitis (AH) is a clinically severe, acute disease that afflicts only a fraction of patients with alcohol use disorder. Genomic studies of alcohol-associated cirrhosis (AC) have identified several genes of large effect, but the genetic and environmental factors that lead to AH and AC, and their degree of genetic overlap, remain largely unknown. This study aims to identify genes and genetic variations that contribute to the development of AH.

Exome-sequencing of patients with AH (N=784) and heavy drinking controls (N=951) identified an exome-wide significant association for AH at patalin-like phospholipase domain containing 3, as previously observed for AC in genome-wide association study, although with a much lower effect size. Single nucleotide polymorphisms (SNPs) of large effect size at inducible T cell costimulatory ligand ( ICOSLG ) (Chr 21) and TOX4/RAB2B (Chr 14) were also exome-wide significant. ICOSLG encodes a co-stimulatory signal for T-cell proliferation and cytokine secretion and induces B-cell proliferation and differentiation. TOX high mobility group box family member 4 ( TOX4 ) was previously implicated in diabetes and immune system function. Other genes previously implicated in AC did not strongly contribute to AH, and the only prominently implicated (but not exome-wide significant) gene overlapping with alcohol use disorder was alcohol dehydrogenase 1B ( ADH1B ). Polygenic signals for AH were observed in both common and rare variant analysis and identified genes with roles associated with inflammation.

This study has identified 2 new genes of high effect size with a previously unknown contribution to alcohol-associated liver disease and highlights both the overlap in etiology between liver diseases and the unique origins of AH.

Apolipoprotein B (ApoB) is essential for the assembly and secretion of triglyceride (TG)-rich VLDL particles, and its dysfunction is linked to metabolic disorders, including dyslipidemia and liver steatosis. However, less attention has been paid to whether and how other apolipoproteins play redundant or compensatory roles when the ApoB function is compromised. Here, we investigated the effects of microsomal triglyceride transfer protein (MTP), which mediates lipidation of nascent ApoB, on ApoE function. We observed a paradoxical increase in ApoE secretion resulting from increased expression in MTP inhibitor (MTPi)-treated human hepatoma cells. This phenotype was recapitulated in APOB-knockout cells and was associated with impaired ApoB secretion. While MTP-dependent transfer of neutral lipids is dispensable for ApoE secretion, TG biosynthesis, redundantly catalyzed by DGAT1 and DGAT2, is required for efficient ApoE secretion in hepatoma cells. ApoE colocalizes with lipid droplets near the Golgi apparatus and mediates TG export in an ApoB-independent fashion. We found that simultaneous inhibition of both ApoE and ApoB, but not inhibition of either alone, led to TG accumulation in hepatoma cells, indicating that both proteins function redundantly to control TG content. Validation studies in primary human hepatocytes (PHHs) demonstrated DGAT2-dependent secretion of ApoE. While MTPi treatment did not elevate ApoE secretion, it induced increased sialylation of ApoE in the supernatants of PHHs. These results show that enhanced ApoE secretion compensates for the impaired ApoB function to maintain the lipid homeostasis, providing an alternative route to modulate lipid turnover in hepatoma cells.

Although metabolic dysfunction-associated steatotic liver disease (MASLD) has been proposed to replace the diagnosis of non-alcoholic fatty liver disease (NAFLD) with new diagnostic criteria since 2023, the genetic predisposition of MASLD remains to be explored.

Participants with data of genome-wide association studies (GWAS) in the Taiwan Biobank database were collected. Patients with missing data, positive for HBsAg, anti-HCV, and alcohol drinking history were excluded. MASLD was defined if having hepatic steatosis on ultrasound, plus at least one of cardiometabolic criteria. The Taiwan biobank used two genetic chips during the period of data collection: Taiwan biobank version 1 (TWBv1) as the initial chip and TWBv2 specifically designed for the Taiwanese population. TWBv2 was used as test group and TWBv1 as validation group. NAFLD fibrosis score (NFS) was used to assess the degree of liver fibrosis, and carotid plaques on duplex ultrasound were employed for the diagnosis of atherosclerosis.

In a total of 16,407 (mean age 55.35 ± 10.41; 29.6% males) participants, 6722 (41.0%) had MASLD. Eleven single-nucleotide polymorphisms (SNP) were identified to be associated with MASLD. Their functions were exonic in two and intronic in nine. They were related to the PNALA3, and SAMM50 genes located on chromosome 22. The linkage disequilibrium showed a high correlation with each other. Four SNPs of PNALA3 and SAMM50 genes had increased risk of MASLD and higher levels of AST/ALT. In addition, there was no association of these two genes with glucose metabolism, but better lipid profiles in SAMM50.

This large GWAS study indicates that eleven SNPs of PNPLA3 and SAMM50 genes predispose the development of MASLD in Taiwanese population.

Metabolic dysfunction-associated steatotic liver disease (MASLD), is one of the most common chronic liver diseases, which encompasses a spectrum of diseases, from metabolic dysfunction-associated steatotic liver (MASL) to metabolic dysfunction-associated steatohepatitis (MASH), and may ultimately progress to MASH-related cirrhosis and hepatocellular carcinoma (HCC). MASLD is a complex disease that is influenced by genetic and environmental factors. Dysregulation of hepatic lipid metabolism plays a crucial role in the development and progression of MASLD. Therefore, the focus of this review is to discuss the links between the genetic variants and DNA methylation of lipid metabolism-related genes and MASLD pathogenesis. We first summarize the interplay between MASLD and the disturbance of hepatic lipid metabolism. Next, we focus on reviewing the role of hepatic lipid related gene loci in the onset and progression of MASLD. We summarize the existing literature around the single nucleotide polymorphisms (SNPs) associated with MASLD identified by genome-wide association studies (GWAS) and candidate gene analyses. Moreover, based on recent evidence from human and animal studies, we further discussed the regulatory function and associated mechanisms of changes in DNA methylation levels in the occurrence and progression of MASLD, with a particular emphasis on its regulatory role of lipid metabolism-related genes in MASLD and MASH. Furthermore, we review the alterations of hepatic DNA and blood DNA methylation levels associated with lipid metabolism-related genes in MASLD and MASH patients. Finally, we introduce potential value of the genetic variants and DNA methylation profiles of lipid metabolism-related genes in developing novel prognostic biomarkers and therapeutic targets for MASLD, intending to provide references for the future studies of MASLD.

Insulin resistance, lipotoxicity, and mitochondrial dysfunction contribute to the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). Mitochondrial dysfunction impairs oxidative phosphorylation and increases reactive oxygen species production, leading to steatohepatitis and hepatic fibrosis. Artificial intelligence (AI) is a potent tool for disease diagnosis and risk stratification.

To investigate mitochondrial DNA polymorphisms in susceptibility to MASLD and establish an AI model for MASLD screening.

Multiplex polymerase chain reaction was performed to comprehensively genotype 82 mitochondrial DNA variants in the screening dataset (n = 264). The significant mitochondrial single nucleotide polymorphism was validated in an independent cohort (n = 1046) using the Taqman® allelic discrimination assay. Random forest, eXtreme gradient boosting, Naive Bayes, and logistic regression algorithms were employed to construct an AI model for MASLD.

In the screening dataset, only mt12361A>G was significantly associated with MASLD. mt12361A>G showed borderline significance in MASLD patients with 2-3 cardiometabolic traits compared with controls in the validation dataset (P = 0.055). Multivariate regression analysis confirmed that mt12361A>G was an independent risk factor of MASLD [odds ratio (OR) = 2.54, 95% confidence interval (CI): 1.19-5.43, P = 0.016]. The genetic effect of mt12361A>G was significant in the non-diabetic group but not in the diabetic group. mt12361G carriers had a 2.8-fold higher risk than A carriers in the non-diabetic group (OR = 2.80, 95%CI: 1.22-6.41, P = 0.015). By integrating clinical features and mt12361A>G, random forest outperformed other algorithms in detecting MASLD [training area under the receiver operating characteristic curve (AUROC) = 1.000, validation AUROC = 0.876].

The mt12361A>G variant increased the severity of MASLD in non-diabetic patients. AI supports the screening and management of MASLD in primary care settings.

Genome-wide association studies (GWAS) have identified common variants associated with metabolic dysfunction-associated steatotic liver disease (MASLD). However, rare coding variant studies have been limited by phenotyping challenges and small sample sizes. We test associations of rare and ultra-rare coding variants with proton density fat fraction (PDFF) and MASLD case-control status in 736,010 participants of diverse ancestries from the UK Biobank, All of Us, and BioMe and performed a trans-ancestral meta-analysis. We then developed models to accurately predict PDFF and MASLD status in the UK Biobank and tested associations with these predicted phenotypes to increase statistical power.

The trans-ancestral meta-analysis with PDFF and MASLD case-control status identifies two single variants and two gene-level associations in APOB, CDH5, MYCBP2, and XAB2. Association testing with predicted phenotypes, which replicates more known genetic variants from GWAS than true phenotypes, identifies 16 single variants and 11 gene-level associations implicating 23 additional genes. Two variants were polymorphic only among African ancestry participants and several associations showed significant heterogeneity in ancestry and sex-stratified analyses. In total, we identified 27 genes, of which 3 are monogenic causes of steatosis (APOB, G6PC1, PPARG), 4 were previously associated with MASLD (APOB, APOC3, INSR, PPARG), and 23 had supporting clinical, experimental, and/or genetic evidence.

Our results suggest that trans-ancestral association analyses can identify ancestry-specific rare and ultra-rare coding variants in MASLD pathogenesis. Furthermore, we demonstrate the utility of machine learning in genetic investigations of difficult-to-phenotype diseases in trans-ancestral biobanks.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the umbrella term that comprises metabolic dysfunction-associated steatotic liver, or isolated hepatic steatosis, through to metabolic dysfunction-associated steatohepatitis, the progressive necroinflammatory disease form that can progress to fibrosis, cirrhosis and hepatocellular carcinoma. MASLD is estimated to affect more than one-third of adults worldwide. MASLD is closely associated with insulin resistance, obesity, gut microbial dysbiosis and genetic risk factors. The obesity epidemic and the growing prevalence of type 2 diabetes mellitus greatly contribute to the increasing burden of MASLD. The treatment and prevention of major metabolic comorbidities such as type 2 diabetes mellitus and obesity will probably slow the growth of MASLD. In 2023, the field decided on a new nomenclature and agreed on a set of research and action priorities, and in 2024, the US FDA approved the first drug, resmetirom, for the treatment of non-cirrhotic metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis. Reliable, validated biomarkers that can replace histology for patient selection and primary end points in MASH trials will greatly accelerate the drug development process. Additionally, noninvasive tests that can reliably determine treatment response or predict response to therapy are warranted. Sustained efforts are required to combat the burden of MASLD by tackling metabolic risk factors, improving risk stratification and linkage to care, and increasing access to therapeutic agents and non-pharmaceutical interventions.

Triglyceride-rich lipoproteins (TRLs) play essential roles in human health and disease by transporting bulk lipids into the circulation. This review summarizes the fundamental mechanisms and diverse factors governing lipoprotein production, secretion, and regulation. Emphasizing the broader implications for human health, we outline the intricate landscape of lipoprotein research and highlight the potential coordination between the biogenesis and transport of TRLs in physiology, particularly the unexpected coupling of metabolic enzymes and transport machineries. Challenges and opportunities in lipoprotein biology with respect to inherited diseases and viral infections are also discussed. Further characterization of the biogenesis and transport of TRLs will advance both basic research in lipid biology and translational medicine for metabolic diseases.

The co-occurrence of metabolic dysfunction and neurodegenerative diseases suggests a genetic link, yet the shared genetic architecture and causality remain unclear. We aimed to comprehensively characterise these genetic relationships.

We investigated genetic correlations among four neurodegenerative diseases and seven metabolic dysfunctions, followed by bidirectional Mendelian randomisation (MR) to assess potential causal relationships. Pleiotropy analysis (PLACO) was used to detect the pleiotropic effects of genetic variants. Significant pleiotropic loci were refined and annotated using functional mapping and annotation (FUMA) and Bayesian colocalisation analysis. We further explored mapped genes with tissue-specific expression and gene set enrichment analyses.

We identified significant genetic correlations in nine out of 28 trait pairs. MR suggested causal relationships between specific trait pairs. Pleiotropy analysis revealed 25 931 significant single-nucleotide polymorphisms, with 246 pleiotropic loci identified via FUMA and 55 causal loci through Bayesian colocalisation. These loci are involved in neurotransmitter transport and immune response mechanisms, notably the missense variant rs41286192 in SLC18B1. The tissue-specific analysis highlighted the pancreas, left ventricle, amygdala, and liver as critical organs in disease progression. Drug target analysis linked 74 unique genes to existing therapeutic agents, while gene set enrichment identified 189 pathways related to lipid metabolism, cell differentiation and immune responses.

Our findings reveal a shared genetic basis, pleiotropic loci, and potential causal relationships between metabolic dysfunction and neurodegenerative diseases. These insights highlight the biological connections underlying their phenotypic association and offer implications for future research to reduce the risk of neurodegenerative diseases.

Metabolic dysfunction-associated steatohepatitis (MASH) represents a progressive form of steatotic liver disease which increases the risk for fibrosis and advanced liver disease. The accumulation of discrete species of bioactive lipids has been postulated to activate signaling pathways that promote inflammation and fibrosis. However, the key pathogenic lipid species is a matter of debate. We explored candidates using various dietary, molecular, and genetic models. Mice fed a choline-deficient L-amino acid-defined high-fat diet (CDAHFD) developed steatohepatitis and manifested early markers of liver fibrosis associated with increased cholesterol content in liver lipid droplets within 5 days without any changes in total liver cholesterol content. Treating mice with antisense oligonucleotides (ASOs) against Coenzyme A synthase (Cosay) or treatment with bempedoic acid or atorvastatin decreased liver lipid droplet cholesterol content and prevented CDAHFD-induced MASH and the fibrotic response. All these salutary effects were abrogated with dietary cholesterol supplementation. Analysis of human liver samples demonstrated that cholesterol in liver lipid droplets was increased in humans with MASH and liver fibrosis and was higher in PNPLA3 I148M (variants rs738409) than in HSD17B13 variants (rs72613567). Together, these data identify cholesterol in liver lipid droplets as a critical mediator of MASH and demonstrate that COASY knockdown and bempedoic acid are novel therapeutic approaches to reduce liver lipid droplet cholesterol content and thereby prevent the development of MASH and liver fibrosis.

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease linked to fibrosis. The role of specific lipid species in its pathogenesis remains debated. Using dietary, molecular, and genetic models, we found that mice on a choline-deficient, high-fat diet (CDAHFD) developed steatohepatitis and early fibrosis, marked by increased cholesterol in liver lipid droplets within five days. Targeting COASY with antisense oligonucleotides or treating with bempedoic acid or atorvastatin reduced lipid droplet cholesterol and prevented MASH. However, dietary cholesterol supplementation negated these effects. Human liver samples confirmed elevated lipid droplet cholesterol in MASH and fibrosis, especially in PNPLA3 I148M carriers. These findings highlight cholesterol reduction as a potential MASH therapy.

The pancreas, an organ with dual functions, regulates blood glucose levels through the endocrine system by secreting hormones such as insulin and glucagon. It also aids digestion through the exocrine system by secreting digestive enzymes. Complex interactions and signaling mechanisms between the endocrine and exocrine functions of the pancreas play a crucial role in maintaining metabolic homeostasis and overall health. Compelling evidence indicates direct and indirect crosstalk between the endocrine and exocrine parts, influencing the development of diseases affecting both. From a developmental perspective, the exocrine and endocrine parts share the same origin-the "tip-trunk" domain. In certain circumstances, pancreatic exocrine cells may transdifferentiate into endocrine-like cells, such as insulin-secreting cells. Additionally, several pancreatic diseases, including pancreatic cancer, pancreatitis, and diabetes, exhibit potential relevance to both endocrine and exocrine functions. Endocrine cells may communicate with exocrine cells directly through cytokines or indirectly by regulating the immune microenvironment. This crosstalk affects the onset and progression of these diseases. This review summarizes the history and milestones of findings related to the exocrine and endocrine pancreas, their embryonic development, phenotypic transformations, signaling roles in health and disease, the endocrine-exocrine crosstalk from the perspective of diseases, and potential therapeutic targets. Elucidating the regulatory mechanisms of pancreatic endocrine and exocrine signaling and provide novel insights for the understanding and treatment of diseases.

Dyslipidemias are often diagnosed based on an individual's lipid panel that may or may not include Lp(a) or apoB. But these values alone omit key information that can underestimate risk and misdiagnose disease, which leads to imprecise medical therapies that reduce efficacy with unnecessary adverse events. For example, knowing whether an individual's dyslipidemia is monogenic can granularly inform risk and create opportunities for precision therapeutics. This review explores the canonical and non-canonical causes of dyslipidemias and how they impact atherosclerotic cardiovascular disease (ASCVD) risk. This review emphasizes the multitude of genetic causes that cause primary hypercholesterolemia, hypertriglyceridemia, and low or elevated high-density lipoprotein (HDL)-cholesterol levels. Within each of these sections, this review will explore the evidence linking these genetic conditions with ASCVD risk. Where applicable, this review will summarize approved therapies for a particular genetic condition.

In managing metabolic dysfunction-associated steatotic liver disease, which affects over 30% of the general population, effective noninvasive biomarkers for assessing disease severity, monitoring disease progression, predicting the development of liver-related complications, and assessing treatment response are crucial. The advantage of simple fibrosis scores lies in their widespread accessibility through routinely performed blood tests and extensive validation in different clinical settings. They have shown reasonable accuracy in diagnosing advanced fibrosis and good performance in excluding the majority of patients with a low risk of liver-related complications. Among patients with elevated serum fibrosis scores, a more specific fibrosis and imaging biomarker has proved useful to accurately identify patients at risk of liver-related complications. Among specific fibrosis blood biomarkers, enhanced liver fibrosis is the most widely utilized and has been approved in the United States as a prognostic biomarker. For imaging biomarkers, the availability of vibration-controlled transient elastography has been largely improved over the past years, enabling the use of liver stiffness measurement (LSM) for accurate assessment of significant and advanced fibrosis, and cirrhosis. Combining LSM with other routinely available blood tests enhances the ability to diagnose at-risk metabolic dysfunction-associated steatohepatitis and predict liver-related complications, some reaching an accuracy comparable to that of liver biopsy. Magnetic resonance imaging-based modalities provide the most accurate quantification of liver fibrosis, though the current utilization is limited to research settings. Expanding their future use in clinical practice depends on factors such as cost and facility availability.

The common genetic variant rs641738 C>T is a risk factor for metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASH), including liver fibrosis, and is associated with decreased expression of the phospholipid-remodeling enzyme MBOAT7 (LPIAT1). However, whether restoring MBOAT7 expression in established metabolic dysfunction-associated steatotic liver disease dampens the progression to liver fibrosis and, importantly, the mechanism through which decreased MBOAT7 expression exacerbates MASH fibrosis remain unclear.

We first showed that hepatocyte MBOAT7 restoration in mice with diet-induced steatohepatitis slows the progression to liver fibrosis. Conversely, when hepatocyte-MBOAT7 was silenced in mice with established hepatosteatosis, liver fibrosis but not hepatosteatosis was exacerbated. Mechanistic studies revealed that hepatocyte-MBOAT7 restoration in MASH mice lowered hepatocyte-TAZ (WWTR1), which is known to promote MASH fibrosis. Conversely, hepatocyte-MBOAT7 silencing enhanced TAZ upregulation in MASH. Finally, we discovered that changes in hepatocyte phospholipids due to MBOAT7 loss-of-function promote a cholesterol trafficking pathway that upregulates TAZ and the TAZ-induced profibrotic factor Indian hedgehog (IHH). As evidence for relevance in humans, we found that the livers of individuals with MASH carrying the rs641738-T allele had higher hepatocyte nuclear TAZ, indicating higher TAZ activity and increased IHH mRNA.

This study provides evidence for a novel mechanism linking MBOAT7-LoF to MASH fibrosis, adds new insight into an established genetic locus for MASH, and, given the druggability of hepatocyte TAZ for MASH fibrosis, suggests a personalized medicine approach for subjects at increased risk for MASH fibrosis due to inheritance of variants that lower MBOAT7.

The global epidemic of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing worldwide. People with MASLD can progress to cirrhosis and hepatocellular carcinoma and are at increased risk of developing type 2 diabetes, cardiovascular disease, chronic kidney disease, and extrahepatic cancers. Most people with MASLD die from cardiac-related causes. This outcome is attributed to the shared pathogenesis of MASLD and cardiometabolic diseases, involving unhealthy dietary habits, dysfunctional adipose tissue, insulin resistance, and subclinical inflammation. In addition, the steatotic and inflamed liver affects the vasculature and heart via increased glucose production and release of procoagulant factors, dyslipidaemia, and dysregulated release of hepatokines and microRNAs. However, there is substantial heterogeneity in the contributors to the pathophysiology of MASLD, which might influence its rate of progression, its relationship with cardiometabolic diseases, and the response to therapy. The most effective non-pharmacological treatment approaches for people with MASLD include weight loss. Paradoxically, some effective pharmacological approaches to improve liver health in people with MASLD are associated with no change in bodyweight or even with weight gain, and similar response heterogeneity has been observed for changes in cardiometabolic risk factors. In this Review, we address the heterogeneity of MASLD with respect to its pathogenesis, outcomes, and metabolism-based treatment responses. Although there is currently insufficient evidence for the implementation of precision medicine for risk prediction, prevention, and treatment of MASLD, we discuss whether knowledge about this heterogeneity might help achieving this goal in the future.

Metabolic dysfunction-associated steatotic liver disease (MASLD), is the most common cause of liver disease, and its burden on health systems worldwide continues to rise at an alarming rate. MASLD is a complex disease in which the interactions between susceptible genes and the environment influence the disease phenotype and severity. Advances in human genetics over the past few decades have provided new opportunities to improve our understanding of the multiple pathways involved in the pathogenesis of MASLD. Notably, the PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 single nucleotide polymorphisms have been demonstrated to be robustly associated with MASLD development and disease progression. These genetic variants play crucial roles in lipid droplet remodeling, secretion of hepatic very low-density lipoprotein and lipogenesis, and understanding the biology has brought new insights to this field. This review discusses the current body of knowledge regarding these genetic drivers and how they can lead to development of MASLD, the complex interplay with metabolic factors such as obesity, and how this information has translated clinically into the development of risk prediction models and possible treatment targets.

Impaired hepatic expression of protein tyrosine phosphatase delta (PTPRD) is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection. However, the PTPRD-expressing hepatic cell types, signalling pathways responsive to PTPRD and their role in non-viral liver disease are largely unknown.

We studied PTPRD expression in single-cell and bulk liver transcriptomic data from mice and humans, and established a Ptprd-deficient mouse model for metabolic dysfunction-associated steatohepatitis (MASH). Identified pathways were validated by perturbation studies in human hepatocytes and PTPRD substrates by pull-down assays. The clinical relevance was further explored in a cohort with metabolic disease by ranking patients according to PTPRD expression and analysing its association with metabolic disease markers.

The analysis of individuals ranked according to PTPRD expression and Ptprd-deficient mice, showed that PTPRD levels were associated with hepatic glucose/lipid signalling and peroxisome function. Hepatic PTPRD expression is impaired in aetiologies of chronic liver diseases that are associated with metabolic disease. We further validated PTPRD as a STAT3 phosphatase in the liver, acting as a regulator of peroxisomal fatty acid metabolism. During MASH, low PTPRD led to increased liver steatosis in Ptprd+/- mice and a pronounced unfolded protein response, which impacts insulin signalling. Accordingly, silencing of PTPRD blunted insulin-induced AKT phosphorylation. Patients with obesity and low hepatic PTPRD expression exhibit increased levels of metabolic risk factors.

Our data revealed an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis, which is recapitulated in clinical manifestations of metabolic liver disease.