UNASSIGNED: Recent studies have found that thyroid function may be associated with the occurrence and development of advanced liver fibrosis in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). However, the majority of such research has consisted of cross-sectional studies. This retrospective cohort study aimed to investigate the effect of low-normal thyroid function on advanced liver fibrosis in MAFLD patients over a 5-year period.
UNASSIGNED: This retrospective cohort study enrolled 825 outpatients and inpatients with MAFLD who attended the Third Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) between January 2011 and December 2018. Based on plasma thyroid hormone and thyroid-stimulating hormone levels, these patients were divided into two groups, namely a low-normal thyroid function group and a strict-normal thyroid function group. The fibrosis-4 score was used to assess advanced liver fibrosis. A chi-square test was conducted to compare the occurrence of advanced fibrosis between the groups.
UNASSIGNED: Among the 825 MAFLD patients, 117 and 708 were defined as having low-normal thyroid function and strict-normal thyroid function, respectively. Follow-up data were available for 767 patients (93.0%) during a 5-year period. Eight (7.5%) MAFLD patients with low-normal thyroid function and 26 (3.9%) with strict-normal thyroid function developed advanced liver fibrosis and the cumulative incidence was not significantly different (P = 0.163). Stratification analysis showed that the lean MAFLD patients (body mass index ≤ 23 kg/m2) with low-normal thyroid function had a higher risk of advanced liver fibrosis than the lean MAFLD patients with strict-normal thyroid function (P < 0.05).
UNASSIGNED: Low-normal thyroid function is associated with advanced liver fibrosis among lean MAFLD patients.

The liver plays an important role in whole-body glucose homeostasis by taking up glucose from and releasing glucose into the blood circulation. In the postprandial state, excess glucose in the blood circulation is stored in hepatocytes as glycogen. In the postabsorptive state, the liver produces glucose by breaking down glycogen and from noncarbohydrate precursors such as lactate. In metabolic diseases such as diabetes, these processes are dysregulated, resulting in abnormal blood glucose levels. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) are noninvasive techniques that give unique insight into different aspects of glucose metabolism, such as glycogenesis, glycogenolysis, and gluconeogenesis, in the liver in vivo. Using these techniques, liver glucose metabolism has been studied in regard to a variety of interventions, such as fasting, meal intake, and exercise. Moreover, deviations from normal hepatic glucose metabolism have been investigated in both patients with type 1 and 2 diabetes, as well as the effects of antidiabetic medications. This review provides an overview of current MR techniques to measure hepatic glucose metabolism and the insights obtained by the application of these techniques in the healthy and diabetic liver.

Alteration of gut microflora results in a metabolic imbalance in the liver. In the present study, we investigate the reversal potential of alteration of the colonic microflora via improving metabolism balance and regulating the altered tight junction of the intestinal tract. Animals were fed with high sugar diet to mimic the onset of the pathophysiological conditions of diabetes. Following induction, animals were divided into two reversal groups i.e., crude cefdinir and colon-specific formulated cefdinir, to alter the gut microflora. In the present study, we have tried to quantify the microbial content via metagenome analysis to provide an actual picture of the alteration and subsequent reversal. Expression of mRNA of junctional protein and parameters involved in liver metabolism was determined using qPCR. Results indicated direct effect of altered composition of gut microflora on the gut permeability and metabolic alteration. Metagenomic analysis showed least evenness and richness in the HSD group whereas antibiotic-treated groups showed reversal of microflora towards control group with increased richness, evenness and decreased distance on PCoA plot. This changes in gut microflora composition changes expression of metabolic markers and thus insulin sensitivity. Targeting colonic microflora to have a reversal effect on T2D pathogenesis, found to have a positive impact on liver metabolic state with improved permeability markers of gut with SCFA alteration.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s12088-022-01032-x.

Background and Aim: More than half of the small-molecule kinase inhibitors (KIs) induced liver injury clinically. Meanwhile, studies have shown a close relationship between mitochondrial damage and drug-induced liver injury (DILI). We aimed to study KIs and the binding between drugs and mitochondrial proteins to find factors related to DILI occurrence. Methods: A total of 1,223 oral FDA-approved drugs were collected and analyzed, including 44 KIs. Fisher\'s exact test was used to analyze DILI potential and risk of different factors. A total of 187 human mitochondrial proteins were further collected, and high-throughput molecular docking was performed between human mitochondrial proteins and drugs in the data set. The molecular dynamics simulation was used to optimize and evaluate the dynamic binding behavior of the selected mitochondrial protein/KI complexes. Results: The possibility of KIs to produce DILI is much higher than that of other types (OR = 46.89, p = 9.28E-13). A few DILI risk factors were identified, including molecular weight (MW) between 400 and 600, the defined daily dose (DDD) ≥ 100 mg/day, the octanol-water partition coefficient (LogP) ≥ 3, and the degree of liver metabolism (LM) more than 50%. Drugs that met this combination of rules were found to have a higher DILI risk than controls (OR = 8.28, p = 4.82E-05) and were more likely to cause severe DILI (OR = 8.26, p = 5.06E-04). The docking results showed that KIs had a significant higher affinity with human mitochondrial proteins (p = 4.19E-11) than other drug types. Furthermore, the five proteins with the lowest docking score were selected for molecular dynamics simulation, and the smallest fluctuation of the backbone RMSD curve was found in the protein 5FS8/KI complexes, which indicated the best stability of the protein 5FS8 bound to KIs. Conclusions: KIs were found to have the highest odds ratio of causing DILI. MW was significantly related to the production of DILI, and the average docking scores of KI drugs were found to be significantly different from other classes. Further analysis identified the top binding mitochondrial proteins for KIs, and specific binding sites were analyzed. The optimization of molecular docking results by molecular dynamics simulation may contribute to further studying the mechanism of DILI.

OBJECTIVE: We evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to identify influential pathways in different preclinical murine models and their relevance in humans.
METHODS: Different models of diet-induced NAFLD (high-fat diet, choline-deficient high-fat diet, Western diet or Western diet supplemented with fructose and glucose in drinking water) were compared with a control diet in male and female mice. We performed metabolic phenotyping, including plasma biochemistry and liver histology, untargeted large-scale approaches (liver metabolome, lipidome and transcriptome), gene expression profiling and network analysis to identify sex-specific pathways in the mouse liver.
RESULTS: The different diets induced sex-specific responses that illustrated an increased susceptibility to NAFLD in male mice. The most severe lipid accumulation and inflammation/fibrosis occurred in males receiving the high-fat diet and Western diet, respectively. Sex-biased hepatic gene signatures were identified for these different dietary challenges. The peroxisome proliferator-activated receptor α (PPARα) co-expression network was identified as sexually dimorphic, and in vivo experiments in mice demonstrated that hepatocyte PPARα determines a sex-specific response to fasting and treatment with pemafibrate, a selective PPARα agonist. Liver molecular signatures in humans also provided evidence of sexually dimorphic gene expression profiles and the sex-specific co-expression network for PPARα.
CONCLUSIONS: These findings underscore the sex specificity of NAFLD pathophysiology in preclinical studies and identify PPARα as a pivotal, sexually dimorphic, pharmacological target.
BACKGROUND: NCT02390232.

BACKGROUND: Microdialysis is a method used to monitor hepatic tissue metabolism. Membranes with a molecular cut-off of 20 kilodalton (kDa) are currently used to measure the small metabolites glucose, glycerol, lactate and pyruvate. Using membranes with higher cut-off such as 100 kDa allows the possibility of measuring larger molecules but may affect results regarding small molecules. The aim was to compare microdialysis catheters with a cut-off of 20 and 100 kDa in the measurement of small molecules in a pig liver model.
METHODS: Four microdialysis catheters were inserted into the liver of each pig used in the experiment (n = 6). Two catheters with cut-off of 20 kDa were perfused with Ringer acetate, and two catheters with cut-off of 100 kDa: one perfused with Ringer acetate and one with hydroxyethyl starch (Voluven) at a flow rate of 0·3 μl min(-1). Dialysate samples were collected at 40-min intervals and analysed for glucose, glycerol, lactate and pyruvate.
RESULTS: Compared to the other catheters, the 100-kDa catheters perfused with Ringer acetate tended to measure higher dialysate concentrations of the small molecules, the difference reaching statistical significance in the case of pyruvate. Concentrations measured by the 100-kDa catheters perfused with Voluven were, however, comparable to the 20-kDa catheters.
CONCLUSIONS: Microdialysis catheters with membrane cut-off of 20 and 100 kDa can be used equally in hepatic microdialysis for the monitoring of glucose, glycerol, lactate and pyruvate, and lactate/pyruvate ratio if a high osmotic solution (Voluven) is used to perfuse the 100-kDa catheters.