Severe Hepatic Steatosis Research Articles

β-hydroxybutyrate ameliorates osteoarthritis through activation of the ERBB3 signaling pathway in mice.

The ketogenic diet (KD) has demonstrated efficacy in ameliorating inflammation in rats with osteoarthritis (OA). However, the long-term safety of the KD and the underlying mechanism by which it delays OA remain unclear. We found that while long-term KD could ameliorate OA, it induced severe hepatic steatosis in mice. Consequently, we developed two versions of ketogenic-based diets: KD supplemented with vitamin D and intermittent KD. Both KD supplemented with vitamin D and intermittent KD effectively alleviated OA by significantly reducing the levels of inflammatory cytokines, cartilage loss, sensory nerve sprouting, and knee hyperalgesia without inducing hepatic steatosis. Furthermore, β-hydroxybutyrate (β-HB), a convenient energy carrier produced by adipocytes, could ameliorate OA without causing liver lesions. Mechanistically, β-HB enhanced chondrocyte autophagy and reduced apoptosis through the activation of Erb-B2 receptor tyrosine kinase 3 (ERBB3) signaling pathway; a pathway which was down-regulated in the articular chondrocytes from both OA patients and mice. Collectively, our findings highlighted the potential therapeutic value of β-HB and KD supplemented with vitamin D and intermittent KD approaches for managing OA.

Models incorporating physical, laboratory and gut metabolite markers can be used to predict severe hepatic steatosis in MAFLD patients.

Metabolic-associated fatty liver disease (MAFLD) induced-severe hepatic steatosis poses significant health risks. Early prediction of this condition is crucial for prompt intervention. Short-chain fatty acids (SCFAs) and tryptophan are gut metabolites correlated with MAFLD pathogenesis in the gut-liver axis. This study aims to construct prediction models for severe hepatic steatosis by including SCFAs and tryptophan metabolites. This study enrolled 83 participants from the outpatient department in 2023. Physical measurements, serum metabolic and inflammatory markers, metabolites of serum SCFAs and tryptophan were collected. Severe hepatic steatosis was diagnosed using vibration-controlled transient elastography and abdominal sonography. All 40 (48.2%) participants diagnosed with severe hepatic steatosis had MAFLD, while approximately three-quarters of those without severe hepatic steatosis had MAFLD. In comparison to the non-severe hepatic steatosis group, individuals with severe hepatic steatosis exhibited higher levels of waist and arm circumference, serum triglyceride (TG), and lower levels of serum high-density lipoprotein cholesterol (HDL-C) and AST/ALT ratio. They also had higher serum levels of lipopolysaccharide-binding protein, isovaleric acid, and propionic acid, and lower levels of 3-methylvaleric acid, indole-3-propionic acid, and indoxyl sulfate. Models incorporating these markers predicted severe hepatic steatosis. One model additionally included waist circumference and triglyceride-glucose index, while the other incorporated arm circumference and TG/HDL-C ratio. The area under the curve reached 0.958 and 0.938, respectively (p < 0.001). SCFAs and tryptophan metabolites are valuable in predicting severe hepatic steatosis. Further research is needed to investigate the roles of these metabolites in MAFLD.

Irisin as a marker of hepatic steatosis in children with metabolic dysfunction-associated steatotic liver disease.

The purpose of this study was to evaluate irisin, myonectin and high-sensitivity interleukin-6 (hs IL-6) levels in obese children and adolescents and to determine the association of these parameters with metabolic dysfunction-associated steatotic liver disease (MASLD) in children. Sixty-one overweight/obese children with suspected liver disease and seventeen healthy controls were included in the study. MASLD was diagnosed according to the latest consensus. Circulating irisin, myonectin and hs IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). The study group included 38 children meeting MASLD criteria and 23 children without diagnosed hepatic steatosis. The concentrations of the analysed myokines were comparable in the MASLD and non-MASLD groups. Patients with MASLD were further divided according to the severity of hepatic steatosis. Significantly higher levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyltransferase, uric acid and irisin were observed in patients with severe hepatic steatosis compared to mild hepatic steatosis. There were borderline statistically significant positive correlations of irisin with ALT and AST. We revealed that elevated irisin levels were associated with the degree of hepatic steatosis in MASLD. We also found a borderline significant positive association of irisin with liver enzymes.

No Difference in Liver Damage Induced by Isocaloric Fructose or Glucose in Mice with a High-Fat Diet

Background/Objectives: The diverse effects of fructose and glucose on the progression of metabolic dysfunction-associated steatotic liver disease remain uncertain. This study investigated the effects, in animal models, of high-fat diets (HFDs) supplemented with either glucose or fructose. Methods: Six-week-old, male C57BL/6J mice were randomly allocated to four groups: normal diet (ND), HFD, HFD supplemented with fructose (30% w/v, HFD + Fru), and HFD supplemented with glucose (initially 30%, HFD + Glu). After 24 weeks, liver and plasma samples were gathered for analysis. In addition, 39 patients with obesity undergoing bariatric surgery with wedge liver biopsy were enrolled in the clinical study. Results: The HFD + Glu group consumed more water than did the HFD and HFD + Fru groups. Thus, we reduced the glucose concentration from 30% at baseline to 15% at week 2 and 10% starting from week 6. The HFD + Fru and HFD + Glu groups had a similar average caloric intake (p = 0.463). The HFD increased hepatic steatosis, plasma lipid levels, lipogenic enzymes, steatosis-related oxidative stress, hepatic inflammation, and early-stage liver fibrosis. Supplementation with fructose or glucose exacerbated liver damage, but no significant differences were identified between the two. The expression patterns of hepatic ceramides in HFD-fed mice (with or without supplemental fructose or glucose) were similar to those observed in patients with obesity and severe hepatic steatosis or metabolic dysfunction–associated steatohepatitis. Conclusions: Fructose and glucose similarly exacerbated liver damage when added to an HFD. Ceramides may be involved in the progression of hepatic lipotoxicity.

Metabolic Syndrome, Hepatic Steatosis and Testosterone: A Matter of Sex

Hepatic steatosis is considered the hepatic manifestation of metabolic disorders. Its global prevalence is a growing public health concern, estimated to affect over 30% of the population. Steatosis is strictly linked to metabolic dysfunction, leading to the revised terminology of MASLD (metabolic dysfunction-associated steatotic liver disease). The disease often progresses in conjunction with metabolic syndrome components, significantly increasing cardiovascular and overall mortality risks. The interplay between sex hormones and metabolic dysfunction is crucial, with male hypogonadism and female hyperandrogenism exacerbating the risk and severity of hepatic steatosis. In men, testosterone deficiency is associated with increased visceral adiposity and insulin resistance, creating a vicious cycle of metabolic deterioration. Conversely, in women, hyperandrogenism, particularly in conditions like polycystic ovary syndrome, may lead to severe metabolic disturbances, including hepatic steatosis. Estrogen deficiency also contributes to central adiposity and metabolic syndrome. The aim of this paper is to discuss this complex sex-dimorphic relationship.

Comparing ultrasound-derived fat fraction and MRI-PDFF for quantifying hepatic steatosis: a real-world prospective study.

To compare the agreement between ultrasound-derived fat fraction (UDFF) with magnetic resonance proton density fat fraction (MRI-PDFF) for quantification of hepatic steatosis and verify its reliability and diagnostic performance by comparing with MRI-PDFF as the reference standard. This prospective study included a primary analysis of 191 patients who underwent MRI-PDFF and UDFF from February 2023 to February 2024. MRI-PDFF were derived from three liver segment measurements with calculation of an overall median PDFF. UDFF was performed by two different sonographers for each of the six measurements, and the median was taken. Intraclass correlation coefficient (ICC) and Bland-Altman analysis were used to assess agreement. Receiver operating characteristics (ROC) curves were used to evaluate the diagnostic performance of UDFF in detecting different degrees of hepatic steatosis. A total of 176 participants were enrolled in the final cohort of this study (median age, 36.0 years; 82 men, 94 women). The median MRI-PDFF value was 11.3% (interquartile range (IQR) 7.5-18.9); 84.7% patients had a median MRI-PDFF value ≥ 6.4%. The median UDFF measured by different sonographers were 9.5% (IQR: 5.0-18.0) and 9.0% (IQR: 5.0-18.0), respectively. The interobserver agreement of UDFF measurement was excellent agreement (ICC = 0.951 [95% CI: 0.934-0.964], p < 0.001). UDFF was positively strongly correlated with MRI-PDFF with ICC of 0.899 (95% CI: 0.852-0.930). The Bland-Altman analysis showed high agreement between UDFF and MRI-PDFF measurements, with a mean bias of 1.7% (95% LOA, -8.7 to 12.2%). The optimal UDFF cutoff values were 5.5%, 15.5% and 17.5% for detecting MRI-PDFF at historic thresholds of 6.4%, 17.4%, and 22.1%, with AUC of 0.851, 0.952, and 0.948, respectively. The sensitivity was 79.2%, 87.5%, 88.9%, and specificity was 81.5%, 90.6%, 90.0%, respectively. UDFF is a reliable and accurate method for quantification and classification of hepatic steatosis, with strong agreement to MRI-PDFF. The UDFF cutoff values of 5.5%, 15.5%, and 17.5% provide high sensitivity and specificity for the detection of mild, moderate, and severe hepatic steatosis, respectively. Question Is ultrasound-derived fat fraction (UDFF) reliable for the quantitative detection of hepatic steatosis compared to MRI proton density fat fraction (MRI-PDFF)? Findings UDFF cutoff values of 5.5%, 15.5%, and 17.5% provided high sensitivity and specificity for the detection of mild, moderate, and severe hepatic steatosis, respectively. Clinical relevance UDFF is a reliable and accurate method for quantification and classification of hepatic steatosis, with strong agreement to MRI-PDFF and high reproducibility of liver fat content by different sonographers.

Fagopyrum dibotrys extract improves nonalcoholic fatty liver disease via inhibition of lipogenesis and endoplasmic reticulum stress in high-fat diet-fed mice

ObjectiveThe prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing, presenting a treatment challenge due to limited options. Endoplasmic reticulum (ER) stress and associated lipid metabolism disorders are main causes of NAFLD, making it important to inhibit ER stress for effective treatment. Fagopyrum dibotrys has hypolipidemic, anti-inflammatory and hepatoprotective properties, showing promise in treating NAFLD. However, its effects on ER stress in NAFLD remain unclear. This study used a high-fat diet (HFD) to establish NAFLD mouse models and supplemented with Fagopyrum dibotrys extract (FDE) to evaluate its therapeutic effect and underlying mechanisms.ResultsWe showed that FDE supplementation reduced the severity of hepatic steatosis and lowered triglycerides (TG) and total cholesterol (TC) levels in NAFLD mice. At the molecular level, FDE supplementation reduced hepatic lipid deposition by downregulating lipogenic markers (SREBP-1c, SCD1) and upregulating fatty acid oxidase CPT1α expression. Additionally, FDE treatment inhibited the overexpression of ER stress markers (GRP78, CHOP, and P-EIF2α) in NAFLD mice livers, and blocked the activation of the PERK-EIF2α-CHOP pathway, demonstrating its role in maintaining ER homeostasis. Considering that activation of the PERK pathway could exacerbate lipid deposition, our findings suggest that FDE has a protective effect against hepatic steatosis in NAFLD mice by attenuating ER stress, and the potential mechanism is through inhibiting the PERK pathway.

Appendicular skeletal muscle mass is associated with metabolic dysfunction-associated steatotic liver disease severity in young men: a cross-sectional and longitudinal study.

Although appendicular skeletal muscle mass (ASM) has been linked to the severity of hepatic steatosis, investigations of its correlation among younger age groups are lacking. We aimed to elucidate the role of ASM in determining the severity of metabolic dysfunction-associated steatotic liver disease (MASLD) in younger patients. Retrospective data were collected from patients younger than 35years who visited the Armed Forces Goyang Hospital between June 2022 and February 2024. Steatosis presence was determined by a controlled attenuation parameter score ≥ 250dB/m, and significant fibrosis was identified with liver stiffness measurement > 8.0kPa. ASM was measured using multifrequency bioelectrical impedance analysis (InBody 620). Of 910 participants, 630 were diagnosed with MASLD. Patients with MASLD had lower ASM/fat mass (ASM/F) (1.02 vs. 1.91; p < 0.001), ASM/body mass index (BMI) (0.91 vs. 1.04/m2; p < 0.001), and ASM/body weight (ASM/W) (29.5% vs. 33.8%; p < 0.001) than non-MASLD patients. Additionally, ASM/F, ASM/BMI, and ASM/W significantly decreased with worsening steatosis severity and were notably lower in patients with significant fibrosis. Among 107 patients with MASLD who underwent two examinations with a median interval of 6.0months, those with increased ASM/F showed a higher proportion of steatosis regression and a lower proportion of steatosis worsening than those with decreased ASM/F (steatosis regression, 43.1% vs. 22.9%; worsening, 11.1% vs. 28.6%; p = 0.031). All three ASM indices were significant factors in steatosis regression during the study period. ASM is associated with the severity of steatosis and significant fibrosis in MASLD in young adults < 35years.

Arsenic and young liver: a case report of hepatic steatosis due to arsenic toxicity.

Arsenic toxicity is rare in developed countries. It may be difficult to diagnose due to its heterogenous symptom presentation. We present a case of severe hepatic steatosis and cholestatic hepatitis associated with arsenic toxicity in an adult.

8015 Growth Hormone Axis Dysfunction in PMM2-CDG: Exploring the Role of Dynamic Tests for the Management of Short Stature in Two Pediatric Cases

Abstract Disclosure: G. Del Medico: None. E. Procopio: None. L. Ferri: None. A. Barbato: None. A. Morrone: None. S. Stagi: None. PMM2-CDG is the most prevalent congenital disorder of glycosylation (CDG) and is caused by defective phosphomannomutase2 (PMM2) activity. According to the 2019 guidelines, approximately half of PMM2-CDG patients exhibit short stature and low serum levels of insulin-like growth factor-1 (IGF-1), IGF binding protein 3 (IGFBP3), and acid-labile subunit (ALS). Despite this, there is no expert consensus on the endocrinological management of this condition. We investigated the growth hormone (GH) axis in two 12-year-old female patients with PMM2-CDG. The first patient was compound heterozygote for the most common PMM2 gene variants in Italy, p.(Leu32Arg) and p.(Arg141His). She presented with short stature (&amp;lt; 2 Standard Deviation Score, SDS) and low serum levels of IGF-1 and IGF-BP3 (&amp;lt; 2.5° for age and sex). Bone age was significantly delayed. Tanner stage was prepubertal. Somatotropic response to GH stimulation testing (Levodopa) was normal. After the IGF-1 generation test with recombinant GH, serum IGF-1 increased by 115%. The second patient was compound heterozygote for the known PMM2 pathogenetic variant p.(Ala108Val) and the novel p.(Thr171Asnfs*11) variant (only case described in literature). She presented short stature (&amp;lt; 2 SDS) with near-to-normal IGF-1 and IGF-BP3 serum levels (2.5° for age and sex). Bone age was slightly delayed. Tanner stage was prepubertal. She also exhibited severe obesity, hypertriglyceridemia, and hepatic steatosis. Her somatotropic response to two GH stimulation tests (Levodopa and Arginine) was deficient, probably because of her significant overweight. IGF-1 serum levels didn’t increase after the IGF-1 generation test. Hypoglycosylation in PMM2-CDG impairs the IGF1 system on multiple levels. It destabilizes the ternary complex formed by IGF-1 and glycoproteins IGFBP3 and ALS, therefore reducing the half-life of circulating IGF-1. Hypoglycosylation also reduces IGF1 production by impairing its precursor proIGF-1Ea and its cellular secretion. As a result, PMM2-CDG patients have GH insensitivity, with normal GH production but low levels of IGF-1. However, there is a lack of information in the literature on the use of dynamic tests and hormonal therapies (GH and rhIGF-1) in CDG. The IGF-1 generation test in our patients showed partial GH sensitivity in the first patient and GH insensitivity in the second patient. These observations suggest variability. Some PMM2-CDG patients may benefit from an extended trial with GH therapy, while for GH-insensitive patients a trial with recombinant IGF-1 might be considered. This is one of the first reports that explores the potential role of dynamic tests in PMM2-CDG. As the biochemical effects of hypoglycosylation on the GH-IGF1 pathway are becoming clearer more clinical research is needed to reach a consensus on the management and treatment of short stature in these patients. Presentation: 6/3/2024

Ubiquitin-specific peptidase 25 ameliorates hepatic steatosis by stabilizing peroxisome proliferator-activated receptor alpha

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. USP25 in adipocytes has been proven to be involved in insulin resistance, a noteworthy characteristic of NAFLD. However, the roles of USP25 in NAFLD remain unclear. In this study, we aimed to elucidate the role of USP25 in NAFLD. Hepatic USP25 protein levels were measured in NAFLD patients and models. USP25 expression was manipulated in both mice and cells to evaluate its role in NAFLD. A downstream target of USP25 in NAFLD progression was identified through proteomic profiling analyses and confirmed. Additionally, a USP25 inhibitor was used to determine whether USP25 could be a viable treatment target for NAFLD. We found that USP25 protein levels were significantly decreased in the livers of NAFLD patients and NAFLD model mice. USP25 protein levels were also decreased in both mouse primary hepatocytes and Huh7 cells treated with free fatty acids (FFAs). We also found that Usp25 knockout mice presented much more severe hepatic steatosis when they were fed a high-fat diet. Similarly, knocking down USP25 in Huh7 cell lines aggravated FFA-induced steatosis, whereas USP25 overexpression ameliorated FFA-induced steatosis in Huh7 cell lines. Further proteomic profiling revealed that the PPARα signaling pathway was a downstream target of USP25, which was confirmed in both mice and cell lines. Moreover, USP25 could stabilize PPARα by promoting its deubiquitination. Finally, a USP25 inhibitor exacerbated diet-induced steatosis in mice. In conclusion, USP25 may play a role in NAFLD through the PPARα signaling pathway and could be a potential therapeutic target for NAFLD.

Tangerine Peel-Derived Exosome-Like Nanovesicles Alleviate Hepatic Steatosis Induced by Type 2 Diabetes: Evidenced by Regulating Lipid Metabolism and Intestinal Microflora.

Non-alcoholic fatty liver disease (NAFLD) represents a significant global health burden, exhibiting a strong correlation with insulin resistance, obesity, and type 2 diabetes (T2DM). Despite the severity of hepatic steatosis in T2DM patients, no specific drugs have been approved for clinical treatment of the disease. Tangerine peel is one kind of popular functional food and reported to possess hypoglycemic and lipid-lowering potential. In this study, we investigated the effects of Tangerine-peel-derived exosome-like nanovesicles (TNVs) on hepatic lipotoxicity associated with T2DM. The TNVs was prepared by differential centrifugation of the aqueous extract of Tangerine and chemical properties were characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and LC-MS/MS. The hypoglycemic and lipid-lowering potential of TNVs were possessed by biochemical measurement, RT-PCR, 16S rRNA sequencing, GC/MS, UHPLC-MS/MS, in vivo small animal imaging assay and HE staining. Subsequently, effects of TNVs on lipid accumulation and glycolysis were investigated on 3T3-L1 and AML-12 cells. TNVs significantly inhibited insulin resistance, reduced hepatic lipid accumulation, facilitate intestinal mucosal repair, rescued gut microbiota dysbiosis, regulated colonic SCFA and liver bile acid metabolism in db/db mice. Furthermore, TNVs restored the expression of key genes in glucose and lipid metabolism (ACC, AMPK, CD36, LXRα, PPAR-γ, SREBP-1) while activating the expression of genes related to glycolysis (G6Pase, GLUT2, PCK1, PEPCK) in db/db mice. Further cell-based mechanistic studies revealed that TNVs reduced lipid accumulation in 3T3-L1 and AML-12 cells via regulation of glucose and lipid metabolism-related genes (UCP1, FGFR4, PRDM16, PGC-1α, Tmem26, Cpt1, Cpt2 and PPAR-α). We for the first time demonstrated that TNVs could significantly improve glucose and lipid metabolism via activating the expression of genes related to fatty acid β-oxidation and glycolysis.

Sex differences in Murine MASH evoked by a Fructose-Palmitate-Cholesterol-Enriched Diet

Background/AimsMetabolic syndrome-associated steatotic liver disease (MASLD) and metabolic syndrome-associated steatohepatitis (MASH) have global prevalence rates exceeding 25% and 3-6%, respectively. The introduction of high fructose corn syrup to the diet in the 1970s has been linked to metabolic and hepatic disturbances. Despite these associations, the potential for sex-dependent responses resulting from fructose-containing diets on MASLD/MASH has not been addressed. MethodsFemale and male C57BL/6J mice were fed fructose-palmitate-cholesterol (“FPC-(non-alcoholic steatohepatitis) (NASH)”) diet versus standard chow (SC) for 16 weeks (N=40 mice). At sacrifice, plasma and liver were retrieved, the latter for single nucleus RNA sequencing. Publicly-available data sets of human male and female MASH liver were probed. ResultsThe FPC-NASH diet induced metabolic dysfunction in both female and male mice, with females exhibiting more severe hepatic steatosis (p=0.0262), inflammation (p=0.0206), and fibrosis (p<0.0001). Single-nucleus RNA sequencing revealed distinct sex-specific transcriptional profiles in hepatocytes and stellate cells responding to the FPC-NASH diet compared to the SC diet. In female mice, compared to males, pathways associated with lipid and metabolic processes in hepatocytes and cell-cell communication and adhesion in stellate cells were enriched. Metabolic flux analyses demonstrated reduced bile acid metabolism in female mice and human hepatocytes in FPC-NASH and MASH conditions, respectively, compared to their male counterparts. ConclusionsMolecular profiling of hepatocytes and stellate cells in FPC-NASH diet-fed mice revealed significant sex differences mirrored in human MASH. The identification of intrinsic, within-sex, diet-dependent disparities underscores the critical need to include both male and female subjects in MAFLD/MASH studies and clinical trials. Impact and ImplicationsDespite the importance of metabolic syndrome-associated steatohepatitis (MASH) in impairment of human health, the potential for and mechanisms of sex-dependent responses have yet to be well-studied, particularly with respect to the possible influence of high fructose corn syrup additives to the diet, which has been linked to metabolic and hepatic disturbances. In a mouse model of fructose supplementation to a NASH diet, female mice displayed significantly higher MASH scores (steatosis, inflammation and fibrosis) compared to male mice. Single nucleus RNA sequencing of liver revealed intrinsic, diet-dependent molecular disparities within sex, which were exaggerated when comparing female versus male mice fed the fructose-containing NASH diet; many of these findings were recapitulated in human female versus male MASH patients. Our findings of dysregulated bile acid metabolism and androgen receptor-related within-sex increases in testosterone in female versus male mice fed fructose-NASH diet versus standard chow diet highlight potential mechanistic explanations and therapeutic targets for addressing sex differences and underscore the need to study both sexes in animal models and human MASH.

Can Opportunistic Use of Computed Tomography Help Reveal the Association Between Hepatic Steatosis and Disease Severity in Hospitalized COVID-19 Patients?

To measure hepatic steatosis (HS) in hospitalized COVID-19 patients using unenhanced chest computed tomography (CT) imaging and to evaluate the relationship between disease severity and prognosis in adult patients.This retrospective study included 152 consecutive hospitalized COVID-19 patients with a positive reverse transcriptase polymerase chain reaction (RT-PCR) test. The COVID-19 Reporting and Data System (CO-RADS) and the chest CT score were evaluated. HS measurements were performed based on CT images using a single region of interest placed on the right liver lobe (segments V-VII). HS was defined as a liver attenuation value <40 Hounsfield units. Data were collected and compared with the patients' prognostic parameters.Of the 152 inpatients, 137 patients (90.1%) had a CT score ≥3 and 109 patients (71.7%) had a CO-RADS score ≥4, 43 (28.2%) had HS. All patients with HS (100%) and 94/109 (86.2%) patients without HS had a CT score ≥3. There was a statistically significant difference between the two groups in terms of chest CT score (p=0.006). There was no statistically significant difference between the two groups in terms of CO-RADS score (p=0.291). The median CRP levels were significantly increased in patients with HS compared to patients without HS (p=0.023). There was no significant difference in ICU hospitalization and mortality due to the presence of HS (p>0.05).The current study revealed significantly higher chest CT scores in COVID-19 patients with HS measured on CT compared to those without HS. Opportunistic use of CT images for the detection of HS can be considered as an adjunctive tool in the risk analysis of COVID-19 patients hospitalized due to COVID-19 pneumonia.The severity of COVID-19 disease is increased in hospitalized patients with hepatosteatosis compared to patients with a normal liver. Density measurements for the evaluation of HS using opportunistic CT applications can be considered as an adjunctive tool in the prognostic evaluation of hospitalized patients with COVID-19 pneumonia. · Parlak AE, Erdem Toslak İ, Turkoglu Selcuk N. Can Opportunistic Use of Computed Tomography Help Reveal the Association Between Hepatic Steatosis and Disease Severity in Hospitalized COVID-19 Patients?. Fortschr Röntgenstr 2024; DOI 10.1055/a-2369-8377.

Multi-dimensional comparison of abdominal obesity indices and insulin resistance indicators for assessing NAFLD

BackgroundThe prevalence of non-alcoholic fatty liver disease (NAFLD) keeps increasing annually worldwide. Non-invasive assessment tools for evaluating the risk and severity of the disease are still limited. Insulin resistance (IR) and abdominal obesity (ABO) are closely related to NAFLD.MethodsA retrospective large-scale, population-based study was conducted based on the data from the 2017–2018 cycle of the National Health and Nutrition Examination Survey (NHANES). Three ABO indices, namely lipid accumulation product (LAP), visceral obesity index (VAI), waist circumference-triglyceride index (WTI), and three IR indices, including triglyceride glucose index (TyG), homeostasis model assessment of insulin resistance (HOMA-IR) and metabolic score for insulin resistance (METS-IR), were analyzed and compared for their relationships with NAFLD based on weighted multivariable logistic regression, spearman correlation heatmap, smooth curve fittings. The area under the curve (AUC) of receiver-operating characteristic (ROC) curve was used to evaluate the diagnostic capability of these indices for NAFLD. Differences among the AUCs were calculated and compared by Delong test.ResultsIn total, 3095 participants were included in our study among which 1368 adults were diagnosed with NAFLD. All six indices presented positive associations with NAFLD. There was a claw-shaped curve between HOMA-IR, VAI, LAP and NAFLD while a smooth semi-bell curve was observed in TyG, METS-IR and WTI. LAP and HOMA-IR had the best diagnostic capability for NAFLD (LAP: AUC = 0.8, Youden index = 0.48; HOMA-IR: AUC = 0.798, Youden index = 0.472) while VAI (AUC = 0.728, Youden index = 0.361) showed the lowest predictive value. The correlation heat map indicated positive correlations between all six indices and liver function, hepatic steatosis and fibrosis severity. In the NAFLD group, IR indicators presented a stronger association with alanine aminotransferase (ALT) compared with ABO indices.ConclusionsAll six indices can screen NAFLD withLAP and HOMA-IR being possibly optimal predictors. IR indices may be more sensitive to identify acute hepatic injury in NAFLD patients than ABO indices.

Hypertriglyceridemia Results From an Impaired Catabolism of Triglyceride-Rich Lipoproteins in PLIN1-Related Lipodystrophy.

Pathogenic variants in PLIN1-encoding PLIN1 (perilipin-1) are responsible for an autosomal dominant form of familial partial lipodystrophy (FPL) associated with severe insulin resistance, hepatic steatosis, and important hypertriglyceridemia. This study aims to decipher the mechanisms of hypertriglyceridemia associated with PLIN1-related FPL. We performed an in vivo lipoprotein kinetic study in 6 affected patients compared with 13 healthy controls and 8 patients with type 2 diabetes. Glucose and lipid parameters, including plasma LPL (lipoprotein lipase) mass, were measured. LPL mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 PLIN1-mutated FPL and 3 controls. Patients with PLIN1-mutated FPL presented with decreased fat mass, insulin resistance, and diabetes (glycated hemoglobin A1c, 6.68±0.70% versus 7.48±1.63% in patients with type 2 diabetes; mean±SD; P=0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; P<0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, P=0.006). Compared with controls, patients with PLIN1-related FPL had a significant reduction of the indirect fractional catabolic rate of VLDL (very-low-density lipoprotein)-apoB100 toward IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein; 1.79±1.38 versus 5.34±2.45 pool/d; P=0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; P=0.005). VLDL-apoB100 production was not different between patients with PLIN1-related FPL and controls. Compared with patients with type 2 diabetes, patients with PLIN1-related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 (P=0.031) and IDL-apoB100 (P=0.031). Plasma LPL mass was significantly lower in patients with PLIN1-related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; P<0.0001), although the LPL protein expression in adipose tissue was similar. VLDL-apoB100 and IDL-apoB100 indirect fractional catabolic rates were negatively correlated with plasma triglycerides and positively correlated with LPL mass. We show that hypertriglyceridemia associated with PLIN1-related FPL results from a marked decrease in the catabolism of triglyceride-rich lipoproteins (VLDL and IDL). This could be due to a pronounced reduction in LPL availability, related to the decreased adipose tissue mass.

Hepatic Steatosis Severity Measured by Ultrasound Attenuation Imaging is Associated With Severity of Atherogenic Dyslipidaemia

Hepatic Steatosis Severity Measured by Ultrasound Attenuation Imaging is Associated With Severity of Atherogenic Dyslipidaemia

Apolipoprotein H deficiency exacerbates alcohol-induced liver injury via gut Dysbiosis and altered bile acid metabolism

BackgroundAPOH plays an essential role in lipid metabolism and the transport of lipids in the circulation. Previous studies have shown that APOH deficiency causes fatty liver and gut microbiota dysbiosis in mouse models. However, the role and potential mechanisms of APOH deficiency in the pathogenesis of alcoholic liver disease remain unclear. MethodsC57BL/6 WT and ApoH−/− mice were used to construct the binge-on-chronic alcohol feeding model. Mouse liver transcriptome, targeted bile acid metabolome, and 16S gut bacterial taxa were assayed and analyzed. Open-source human liver transcriptome dataset was analyzed. ResultsApoH−/− mice fed with alcohol showed severe hepatic steatosis. Liver RNAseq and RT-qPCR data indicated that APOH deficiency predominantly impacts hepatic lipid metabolism by disrupting de novo lipogenesis, cholesterol processing, and bile acid metabolism. A targeted bile acid metabolomics assay indicated significant changes in bile acid composition, including increased percentages of TCA in the liver and DCA in the gut of alcohol-fed ApoH−/− mice. The concentrations of CA, NorCA, and HCA in the liver were higher in ApoH−/− mice on an ethanol diet compared to the control mice (p < 0.05). Additionally, APOH deficiency altered the composition of gut flora, which correlated with changes in the liver bile acid composition in the ethanol-feeding mouse model. Finally, open-source transcript-level data from human ALD livers highlighted a remarkable link between APOH downregulation and steatohepatitis, as well as bile acid metabolism. ConclusionAPOH deficiency aggravates alcohol induced hepatic steatosis through the disruption of gut microbiota homeostasis and bile acid metabolism in mice.

Disturbed intracellular folate homeostasis impairs autophagic flux and increases hepatocytic lipid accumulation

BackgroundMetabolic associated fatty liver disease (MAFLD), a prevalent liver disorder affecting one-third of the global population, encompasses a spectrum ranging from fatty liver to severe hepatic steatosis. Both genetic and lifestyle factors, particularly diet and nutrition, contribute to its etiology. Folate deficiency, a frequently encountered type of malnutrition, has been associated with the pathogenesis of MAFLD and shown to impact lipid deposition. However, the underlying mechanisms of this relationship remain incompletely understood. We investigated the impact of disturbed folate-mediated one-carbon metabolism (OCM) on hepatic lipid metabolism both in vitro using human hepatoma cells and in vivo using transgenic fluorescent zebrafish displaying extent-, stage-, and duration-controllable folate deficiency upon induction.ResultsDisturbed folate-mediated one-carbon metabolism, either by inducing folate deficiency or adding anti-folate drug, compromises autophagy and causes lipid accumulation in liver cells. Disturbed folate status down-regulates cathepsin L, a key enzyme involved in autophagy, through inhibiting mTOR signaling. Interfered mitochondrial biology, including mitochondria relocation and increased fusion-fission dynamics, also occurs in folate-deficient hepatocytes. Folate supplementation effectively mitigated the impaired autophagy and lipid accumulation caused by the inhibition of cathepsin L activity, even when the inhibition was not directly related to folate deficiency.ConclusionsDisruption of folate-mediated OCM diminishes cathepsin L expression and impedes autophagy via mTOR signaling, leading to lipid accumulation within hepatocytes. These findings underscore the crucial role of folate in modulating autophagic processes and regulating lipid metabolism in the liver.

Regional fat distribution and hepatic fibrosis and steatosis severity in patients with nonalcoholic fatty liver disease and type 2 diabetes.

Epidemiologic findings suggest that measures of body fat distribution predict health outcomes independent of the overall body fat assessed by body mass index (BMI). This study aimed to evaluate the associations of overall and regional body fat with the severity of hepatic steatosis and fibrosis in type 2 diabetic patients with non-alcoholic fatty liver disease. Bioelectric impedance analysis and two newly developed anthropometric indices, namely, A Body Shape Index (ABSI) and Body Roundness Index (BRI), were used to estimate the body fat. Based on fibroscan parameters, significant hepatic fibrosis and severe steatosis were defined as ≥F2 and >66%, respectively. Higher total body fat (odds ratio [OR] 1.107, 95% confidence intervals (CI) 1.038-1.182, p=0.002), trunk fat (OR 1.136, 95% CI 1.034-1.248, p=0.008) and leg fat (OR 1.381, 95% CI 1.139-1.674, p=0.001) were associated with liver fibrosis. However, in contrast to the total body fat (OR 1.088, 95% CI 1.017-1.164, p=0.014) and leg fat (OR 1.317, 95% CI 1.066-1.628, p=0.011), the trunk fat was not associated with severe hepatic steatosis. BRI performed better than trunk, leg and total body fat in predicting hepatic steatosis (OR 2.186, 95% CI 1.370-3.487, p=0.001) and fibrosis (OR 2.132, 95% CI 1.419-3.204, p<0.001). Moreover, the trunk to leg fat ratio and ABSI were not independent predictors of either steatosis or fibrosis (p>0.05). BRI revealed a superior predictive ability for identifying the degree of hepatic steatosis and stiffness than other obesity indices. Additionally, higher levels of adiposity in the trunk, legs, and overall body were linked to an increased risk of developing liver fibrosis. Although trunk fat did not show an association with severe hepatic steatosis, an increase in leg and total fat was related to liver steatosis.