Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease.

There is an unmet clinical need for pharmacologic treatment for metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocyte cell death is a hallmark of this highly prevalent chronic liver disease, but the dominant type of cell death remains uncertain. Here we report that ferroptosis, an iron-catalyzed mode of regulated cell death, contributes to MASLD. Unsupervised clustering in a cohort of biopsy-proven MASLD patients revealed a subgroup with hepatic ferroptosis signature and lower glutathione peroxidase 4 (GPX4) levels. Likewise, a subgroup with reduced ferroptosis defenses was discerned in public transcriptomics datasets. Four weeks of choline-deficient L-amino acid-defined high-fat diet (CDAHFD) induced MASLD with ferroptosis in mice. Gpx4 overexpression did not affect steatohepatitis, instead CDAHFD protected from morbidity due to hepatocyte-specific Gpx4 knockout. The ferroptosis inhibitor UAMC-3203 attenuated steatosis and alanine aminotransferase in CDAHFD and a second model, i.e., the high-fat high-fructose diet (HFHFD). The effect of monounsaturated and saturated fatty acids supplementation on ferroptosis susceptibility was assessed in human HepG2 cells. Fat-laden HepG2 showed a drop in ferroptosis defenses, increased phosphatidylglycerol with two polyunsaturated fatty acid (PUFA) lipid tails, and sustained ferroptosis sensitivity. In conclusion, this study identified hepatic ferroptosis as a detrimental factor in MASLD patients. Unexpectedly, non-PUFA supplementation to hepatocytes altered lipid bilayer composition to maintain ferroptosis sensitivity. Based on findings in in vivo models, ferroptosis inhibition represents a promising therapeutic target in MASLD.

Metabolic Dysfunction-Associated Fibrosis 5 (MAF-5) Score Predicts Liver Fibrosis Risk and Outcome in the General Population With Metabolic Dysfunction.

BACKGROUND & AIMS: There is an unmet need for noninvasive tests to improve case-finding and aid primary care professionals in referring patients at high risk of liver disease. METHODS: A metabolic dysfunction-associated fibrosis (MAF-5) score was developed and externally validated in a total of 21,797 individuals with metabolic dysfunction in population-based (National Health and Nutrition Examination Survey 2017-2020, National Health and Nutrition Examination Survey III, and Rotterdam Study) and hospital-based (from Antwerp and Bogota) cohorts. Fibrosis was defined as liver stiffness ≥8.0 kPa. Diagnostic accuracy was compared with FIB-4, nonalcoholic fatty liver disease fibrosis score (NFS), LiverRisk score and steatosis-associated fibrosis estimator (SAFE). MAF-5 was externally validated with liver stiffness measurement ≥8.0 kPa, with shear-wave elastography ≥7.5 kPa, and biopsy-proven steatotic liver disease according to Metavir and Nonalcoholic Steatohepatitis Clinical Research Network scores, and was tested for prognostic performance (all-cause mortality). RESULTS: The MAF-5 score comprised waist circumference, body mass index (calculated as kg / m2), diabetes, aspartate aminotransferase, and platelets. With this score, 60.9% was predicted at low, 14.1% at intermediate, and 24.9% at high risk of fibrosis. The observed prevalence was 3.3%, 7.9%, and 28.1%, respectively. The area under the receiver operator curve of MAF-5 (0.81) was significantly higher than FIB-4 (0.61), and outperformed the FIB-4 among young people (negative predictive value [NPV], 99%; area under the curve [AUC], 0.86 vs NPV, 94%; AUC, 0.51) and older adults (NPV, 94%; AUC, 0.75 vs NPV, 88%; AUC, 0.55). MAF-5 showed excellent performance to detect liver stiffness measurement ≥12 kPa (AUC, 0.86 training; AUC, 0.85 validation) and good performance in detecting liver stiffness and biopsy-proven liver fibrosis among the external validation cohorts. MAF-5 score >1 was associated with increased risk of all-cause mortality in (un)adjusted models (adjusted hazard ratio, 1.59; 95% CI, 1.47-1.73). CONCLUSIONS: The MAF-5 score is a validated, age-independent, inexpensive referral tool to identify individuals at high risk of liver fibrosis and all-cause mortality in primary care populations, using simple variables.

Basal metabolic rate using indirect calorimetry among individuals living with overweight or obesity: The accuracy of predictive equations for basal metabolic rate.

BACKGROUND & AIMS: Weight reduction programs in people with overweight or obesity can be informed by indirect calorimetry (IC) which is the gold standard to measure basal metabolic rate (BMR). Since IC is labor intensive and expensive, predictive equations are often used as an alternative. In this study the accuracy rate was assessed and bias statistics of predictive equations were compared to IC among subjects with overweight or obesity. Secondly, differences in clinical features between individuals with over-, accurate or underestimation of their BMR were evaluated. METHODS: This cross sectional study included 731 subjects from the outpatient obesity clinic of the Antwerp University Hospital, Belgium. Fourteen equations were evaluated. Overestimation and underestimation was defined as >10 % and <10 % of measured BMR. RESULTS: In the total population, mean age was 43 ± 13 years, mean BMI 35.6 ± 5.8 kg/m2 and 79.5 % were female. The highest accuracy rates were reached by the Henry (73 %), Ravussin (73 %) and Mifflin St. Jeor (73 %) equations. In the total population, the Mifflin St. Jeor and Henry equation were unbiased. The Akern, Livingston and Ravussin equations were biased to underestimation. All other equations were biased to overestimation. Subjects with an underestimation of BMR had significantly higher waist-hip ratio (1.02 ± 0.13 vs 0.91 ± 0.11; P < 0.001), higher visceral adipose tissue (239 ± 96 vs 162 ± 93; P < 0.001), lower fat free mass (kg) (67.6 (45.4-95.9) vs 54.0 (39.6-95.5); P < 0.001) and a higher prevalence of the Metabolic Syndrome (24 (77.4) vs 112 (37.5); P < 0.001). Individuals with an overestimation of BMR had significantly higher subcutaneous adipose tissue (545 ± 149 vs 612 ± 149; P < 0.05), lower fasting plasma insulin (81 (10-2019) vs 67 (27-253); P < 0.001) and lower 2-h plasma glucose (132 (30-430) vs 116 (43-193); P < 0.001) during OGTT. CONCLUSIONS: In this study, the Henry and Mifflin St. Jeor equations have the highest accuracy and lowest bias to estimate the basal metabolic rate in a Caucasian, predominantly female, population living with overweight or obesity. Visceral and subcutaneous adipose tissue and presence of metabolic syndrome were significantly different in individuals with over- or underestimation of BMR.