Hypocholesterolemia hallmarks sepsis, though its pathophysiology and tissue-specific consequences are unclear. As low circulating cholesterol may reflect impaired endogenous cholesterol synthesis, we hypothesized that infusion of the cholesterol precursor mevalonate can reverse sepsis-induced hypocholesterolemia, whereby beneficially affecting adrenal and muscle integrity. In a catheterized mouse model of cecal ligation and puncture-induced sepsis (male 24-wk-old C57BL/6J mice), septic mice received either 5-day mevalonate infusion (78 mg/day) or placebo versus healthy controls (n = 50). Plasma high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, corticosterone, total bile acids, adrenocortical lipids, myofiber cholesterol, and muscle force were quantified. Expression markers of cholesterol homeostasis and structural integrity were investigated in adrenal, muscle and liver tissue. Liver mevalonate metabolites were quantified with liquid chromatography-mass spectrometry (LC-MS). Next, a secondary analysis on a prospective observational human study on the time course of adrenal function in the intensive care unit was performed to assess the association between plasma cholesterol and cortisol (n = 47). Also, plasma mevalonate was quantified with LC-MS. In septic mice, 5-day mevalonate infusion worsened HDL and LDL hypocholesterolemia versus placebo (P < 0.05). Decreased hepatic cholesterol synthesis expression markers, apolipoproteins, and hepatic cholesterol concentrations were observed in mevalonate-infused septic mice versus placebo (P < 0.05). No additional effect on plasma corticosterone, bile acids, myofiber cholesterol, and loss of muscle force and adrenocortical lipid depletion was observed. In prolonged sepsis patients, plasma mevalonate was increased, whereas plasma HDL- and LDL-cholesterol were low (P < 0.05) but did not correlate with plasma cortisol. To conclude, mevalonate infusion worsened sepsis-induced hypocholesterolemia, possibly due to increased feedback on hepatic cholesterol synthesis, without aggravating the adrenal or muscle sepsis phenotype.NEW & NOTEWORTHY Prolonged infusion with the cholesterol precursor, mevalonate, worsened hypocholesterolemia in a mouse model of sepsis-induced critical illness, likely due to increased feedback on hepatic cholesterol synthesis. Loss of muscle force and mass was not further affected, nor did mevalonate affect adrenal gland steroidogenic markers and the loss of adrenocortical lipids. In prolonged sepsis patients, sustained HDL and LDL hypocholesterolemia was observed in the face of high plasma mevalonate concentrations, but did not correlate with plasma cortisol.

Glucokinase Regulatory Protein (GKRP) controls the activity of Glucokinase (GCK) to regulate liver glucose uptake and storage. Coding variants in GCKR, the gene encoding GKRP, strongly associate with fatty liver disease, hypertriglyceridemia, and hypercholesterolemia. Here, we sought to investigate the mechanisms by which a common GKRP variant affects hepatic lipid and cholesterol metabolism. We developed mouse models to examine how the human GKRP P446L variant influences liver and systemic metabolism. Endogenous Gckr expression was ablated in adult mouse hepatocytes, together with re-expression of either human GKRP P446L or the reference GKRP protein. We assessed body weight, adiposity, systemic glucose homeostasis, and hepatic metabolites in mice expressing reference GKRP or GKRP P446L under multiple metabolic conditions. To determine whether the effects of GKRP P446L may result from reduced GCK activity, we analyzed mice with liver-specific deletion of Gck. Hepatic expression of GKRP P446L resulted in reduced GKRP and GCK protein levels and elevated serum cholesterol. Hepatic deletion of Gck in mice recapitulated several effects of GKRP P446L, including increased hepatic cholesterol and triglyceride content. The elevated cholesterol was associated with increased cholesterogenic gene expression and cholesterol synthesis. Hepatic expression of an alternative hexokinase (HKII) normalized the effects of GCK-deficiency, suggesting that impaired glucose phosphorylation underlies the phenotype. The GKRP P446L variant reduced GKRP protein abundance, and diminished GCK activity while increasing cholesterol levels. Loss of GCK elevated cholesterol and hepatic triglyceride levels. Collectively, these findings demonstrate that GCK suppresses hepatic cholesterol synthesis and lipid accumulation, suggesting that reduced GCK activity underlies the metabolic abnormalities associated with the GKRP P446L variant.

Our aim was to evaluate the efficacy of the triple glucagon, GIP, and GLP-1 receptor agonist retatrutide in diet-induced obese MASH mouse and hamster models, two preclinical models that we routinely use for assessing new therapies targeting obesity. In mice, retatrutide strongly reduced body weight by 31% (p < 0.0001 vs. vehicle), both fat and lean mass, and food and water intake during the first days of treatment, while energy expenditure was not altered significantly. Retatrutide markedly reduced the HOMA-IR index of insulin resistance, hepatic steatosis score, fatty acids, triglycerides, and total cholesterol content. In hamsters, retatrutide altered food preference with increased chow diet intake and decreased high fat/cholesterol diet and 10% fructose water intake. The significant weight loss was associated with a reduction in fat and lean mass, but the lean mass was not different after 5 weeks of treatment with no change in mineral bone density. Retatrutide significantly reduced HOMA-IR, plasma triglycerides, and LDL-cholesterol levels. Although retatrutide did not reduce histopathological scoring, there was a 50% reduction in hepatic triglyceride content (p < 0.01). Retatrutide demonstrates multiple metabolic benefits in both mouse and hamster models. Our preclinical setting will help to assess the efficacy of novel therapies targeting obesity and MASH.

Abstract This study examined the effects of different food deprivation periods (0, 7, 14, 28, 42, and 84 days) on physical indexes, appetite gene expression, physiological and biochemical levels and intestinal histology in Japanese eel ( Anguilla japonica ). A total of 240 elvers (3.87 ± 0.06 g) were randomly divided into a starvation group (SG) and a feeding group (FG). The results showed that SG exhibited significant declines in body weight, condition factor, and hepatosomatic index with prolonged starvation. During the starvation period, appetite‐related genes exhibited dynamic regulation. Compared to FG, the mRNA expression of neuropeptide Y ( npy ) and ghrelin in SG increased significantly at days 7, 28, and 84, while corticotropin‐releasing hormone ( crh ), pro‐opiomelanocortin ( pomca ), cholecystokinin ( cck ), and peptide YY ( pyy ) decreased significantly at days 7, 14, and 84. Superoxide dismutase and catalase activities in SG peaked at days 7 and 14, respectively, significantly higher than FG, but declined below FG by day 84. Additionally, malondialdehyde levels increased by 85.46% and total antioxidant capacity decreased by 62.88% in SG at day 84 compared with FG. Intestinal histology revealed villus atrophy, goblet cell loss, and structural damage during prolonged food deprivation, while digestive enzymes (protease, amylase, and lipase) in SG were significantly lower than FG. Metabolically, SG exhibited significantly lower glucose and serum triglyceride levels than FG at the 84th day, whereas hepatic cholesterol content was markedly elevated. Furthermore, liver glycogen and muscle glycogen in SG gradually declined, reaching the lowest level at the 84th day. These findings highlighted a specific adaptation strategy, characterized by glycogenolysis and antioxidant activation during short‐term starvation, while long‐term food deprivation led to metabolic collapse, oxidative damage, and intestinal dysfunction. This study elucidated survival strategies under nutritional stress, offering insights for optimizing feeding regimes in A. japonica farming.

Inulin, a natural dietary fiber, confers multiple physiological benefits. However, the effects of inulin on the liver and intestinal health of broilers remain unclear. The study investigated the effects and mechanisms of inulin supplementation on hepatic and intestinal health of broilers. A total of 192 male broilers (821.15 ± 14.99 g) at 21 d of age were randomly allocated to four treatment groups, comprising eight replicates per group with six broilers each. The dietary treatments included: a control group (CON) receiving a basal diet and three treatment groups fed the basal diet supplemented with 0.5, 1.0, or 2.0 g/kg inulin (designated as INU-0.5, INU-1.0, and INU-2.0, respectively). Results indicated that dietary inulin supplementation elicited a quadratic response in final body weight (FBW, P = 0.032). Inulin supplementation produced linear improvements in average daily gain (ADG, P = 0.044) alongside quadratic reductions in both average daily feed intake (ADFI) and feed-to-gain ratio (F/G ratio) (P < 0.001). Notably, inulin supplementation linearly decreased malondialdehyde (MDA) levels (P < 0.001) while significantly enhancing superoxide dismutase (SOD) activity (P < 0.001). Furthermore, inulin supplementation demonstrated dose-dependent effects on lipid metabolism, including a linear reduction in abdominal fat deposition (P < 0.001), decreased hepatic and serum concentrations of total cholesterol (TCHO, both P < 0.001) and triglycerides (TG, P < 0.001 and P = 0.001, respectively), and reduced serum levels of both high-density lipoprotein (HDL, P = 0.010) and low-density lipoprotein (LDL, P < 0.001) (P < 0.01). Parallel improvements in intestinal barrier function were observed, with linear increases in jejunal expression of tight junction proteins (claudin-5, occludin, and zonula occludens-1 [ZO-1]), mucin 2 (MUC2), and diamine oxidase (DAO) (P < 0.001). Additionally, inulin supplementation selectively increased the abundances of key microbes, including Bacteroides, Lactobacillus, and Akkermansia, while decreased the abundances of Alistipes, Odoribacte, Parabacteroides, Rikenella, and Erysipelatoclostridium (P < 0.001). These microbial shifts were associated with modulation of key metabolic pathways, including taurine and hypotaurine metabolism, purine metabolism, arginine and proline, and phenylalanine metabolism. Collectively, these findings demonstrate that inulin supplementation enhances broiler productivity while improving both intestinal and hepatic health (P < 0.05) through microbiota-mediated metabolic regulation. Therefore, dietary inulin supplementation would be a recommendable nutritional strategy to optimize production efficiency in commercial broiler industry.

Chalcone derivative 1m mitigates hepatic fibrosis and inflammation, enhances cholesterol efflux and reduces atherosclerosis.

Glyphosate exposure impairs glucose and lipid metabolism by disturbing the circadian clock system in mice liver.

Introduction and Objective: Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with limited treatment options. While the FDA-approved FGF21 agonist has shown efficacy, its response rate for NASH resolution and fibrosis improvement remains suboptimal. MWN105 is a novel unimolecular triple agonist designed to activate GLP-1, GIP, and FGF21 pathways synergistically, addressing both metabolic dysfunction and fibrosis in NASH. Methods: A highly stable and active FGF21 with combined point mutations was screened out and connected to a GLP-1 and GIP chimeric polypeptide through Fc fusion, resulting in MWN05. MWN105 was evaluated in preclinical models, including diet-induced obese (DIO) mice, B6-Alms1-del NASH mice, and NASH-diabetes nonhuman primates (NHPs). The study assessed liver histology, metabolic biomarkers, body weight, and enzyme activity compared to tirzepatide. Results: In the B6-Alms1-del NASH mouse model, MWN105 significantly reduced body weight, liver weight, and liver-to-body weight ratio. Plasma ALT, AST, CHOL, and LDL-C levels, as well as hepatic cholesterol and triglyceride content, were markedly reduced. Liver NAS scores (steatosis, ballooning) also improved significantly. In NHPs, MWN105 led to a 30-50% reduction in liver fat, a 2.5-point improvement in NAS score, and ≥1-stage fibrosis improvement after 10 weeks. MWN105-treated NHPs also showed 15% weight loss with better lean mass preservation than tirzepatide. In DIO mice, MWN105 resulted in ~30% sustained body weight reduction without rebound, while preserving lean mass better than tirzepatide. Conclusion: MWN105 demonstrates potent metabolic and antifibrotic effects, addressing key NASH pathologies. MWN105 has a potential best-in-class therapeutic profile for NASH. MWN105 has obtained IND clearance in both the U.S. and China and Further Phase I clinical study is on-going. Disclosure W. Song: Employee; Shanghai minwei biotechnology Co,,LTD.

Introduction and Objective: Undernutrition remains a persistent nutritional problem in low-income countries, contributing to disease development, like metabolic dysfunction-associated fatty liver disease (MAFLD). However, the molecular mechanisms underlying the onset of MAFLD in undernutrition are not yet fully understood. This study aims to characterize the role of endoplasmic reticulum (ER)-mitochondria contacts in the onset and progression of MAFLD during undernutrition. Methods: 30-day-old male C57BL6J mice were fed for three months with a diet containing either 14% protein (Control - C) or 6% protein (Protein Restriction - R). Blood and liver samples were collected for functional and molecular analyses. Data were analyzed using Student's t-test or Mann-Whitney test, with statistical significance at P &amp;lt; 0.05. Results: R mice exhibited a 31% reduction in final body weight (P &amp;lt; 0.001) and a 20% decrease in total plasma protein levels (P &amp;lt; 0.05), validating the protein undernutrition model. Protein restriction led to increased hepatic triglyceride (51%, P &amp;lt; 0.05) and cholesterol (44%, P &amp;lt; 0.05) content, elevated alanine transaminase activity (12%, P &amp;lt; 0.05), and higher collagen deposition (28%, P &amp;lt; 0.05), indicative of MAFLD development. Hepatocytes from R mice exhibited greater ER-mitochondria contact (35%, P &amp;lt; 0.05) compared to C mice. This increase was associated with higher reactive oxygen species (ROS) levels (28%, P &amp;lt; 0.05) and reduced basal respiration and maximum mitochondrial capacity (35% and 46%, P &amp;lt; 0.05) in the liver from R mice. Conclusion: These findings demonstrated that protein restriction increases hepatocyte ER-mitochondria contact, enhancing ROS production, impairing mitochondrial metabolism, and contributing to lower fatty acid oxidation. Understanding these mechanisms may pave the way for targeted therapeutic strategies to mitigate MAFLD in undernourished individuals. Disclosure T. Araujo: None. L.M. Barreto dos Santos: None. J.A. Junior: None. E.M. Carneiro: None. Funding FAPESP (2023/02152-4)

Inflammation and apoptosis play crucial role in the progression of liver diseases. This study aimed to evaluate the effects of Interleukin-1 receptor-associated kinase inhibitor (IRAKi) in combination with pioglitazone on the expression of inflammatory and apoptotic markers in the liver of C57BL/6J mice subjected to a high-fat diet (HFD). Male C57BL/6J mice were divided into five groups: Control (normal diet, ND), HFD, HFD-IRAKi, HFD-pioglitazone (HFD-PIO), and HFD-IRAKi-PIO. All groups, except ND, were administered HFD for 12 weeks. Subsequently, IRAKi (2mg/kg, intraperitoneally, three times per week) and pioglitazone (10mg/kg, orally, daily) were administered for 14 days. Gene and protein expression levels were assessed using real-time PCR and western blot analysis. Separate administration of IRAKi and pioglitazone significantly reduced the mRNA levels of inflammatory markers IL-1β, IL-6, TNF-α, and NF-κB (p < 0.001). Combined treatment with IRAKi and pioglitazone significantly reduced hepatic triglyceride (TG) and cholesterol content (p < 0.05) and attenuated expression of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, NF-κB) and apoptotic markers (cleaved-CASPASE3, Bax), while enhancing Il10 expression. These findings support the therapeutic potential of this combination in metabolic liver diseases such as MASLD. Co-administration of IRAKi and PIO attenuated markers of inflammation and apoptosis. These findings highlight the potential of IRAKi and pioglitazone as therapeutic agents for metabolic and inflammatory liver diseases, warranting further clinical evaluation.

Integrative analysis of metabolomics and transcriptomics reveals alterations in egg quality and hepatic lipid metabolism in hens supplemented with curcumin.

ObjectiveMaternal betaine supplementation has been shown to affect offspring metabolism through epigenetic mechanisms in mammals. This study aimed to investigate whether parental betaine supplementation can exert intergenerational effects on hepatic cholesterol metabolism in offspring goslings, and the possible epigenetic modification associated with such effects.MethodsIn this study, 450 female and 90 male Jiangnan White goose breeders, aged 39 weeks, were randomly assigned to three groups receiving basal (control, CON), or betaine-supplemented diets at low (LBT, 2.5 g/kg) or high (HBT, 5 g/kg) levels for 7 weeks. The breeder eggs laid in the last week were collected for incubation. Offspring goslings were slaughtered at 35 and 63 days of age to collect blood, bile, and liver samples for biochemical analysis and gene and protein expression studies.ResultsThe body weight of goslings in the LBT and HBT groups was significantly higher than that in the CON group (p<0.05). Serum and liver total cholesterol contents were significantly decreased in the HBT group (p<0.05), while the total bile acids contents in the liver and bile were significantly increased (p<0.05). These changes were associated with the upregulation of cholesterol-7 alpha-hydroxylase (CYP7A1) and bile salt export protein at both mRNA and protein levels (p<0.05). Additionally, parental betaine supplementation significantly decreased the DNA methylation level on the promoter region of the CYP7A1 gene (p<0.05).ConclusionThese results indicate that parental betaine supplementation decreases hepatic cholesterol content in offspring goslings through epigenetic modulation of the CYP7A1 gene.

High-fat diets (HFDs) usually trigger disruptions in lipid metabolic processes and immune suppression in fish. As an eco-friendly and potent additive, the inclusion of probiotics in fish diets ameliorates dysregulations in lipid metabolism, mitigates oxidative stress, and reduces inflammatory reactions triggered by HFDs. However, little current research has focused on the improvement of the hazards of HFDs in fish by probiotics. Therefore, we employed 4-dimensional data-independent (4D-DIA) proteomic analysis to investigate the mechanism of the protective impact of probiotics against HFD-induced hepatic injury in Coilia nasus between the HFD group and the probiotic supplementation in HFD (PHFD) group. Additionally, lipid accumulation and antioxidant indicators in the liver were also measured via Oil Red O staining and activity detection. Administration of probiotics markedly attenuated the hepatic concentrations of triglycerides (TG), cholesterol (CHO), and low-density lipoprotein cholesterol (LDL-C) in C. nasus subjected to HFDs. Furthermore, it significantly upregulated the expression of the differentially expressed proteins (DEPs) implicated in cholesterol metabolism and fatty acid oxidation, while concurrently downregulating the DEPs associated with fatty acid synthesis. Additionally, probiotic supplementation significantly reduced the aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA) levels induced by HFDs. It also upregulated the activities of catalase (CAT) and superoxide dismutase (SOD). Probiotic supplementation significantly upregulated the DEPs related to antioxidants, while significantly downregulating the DEPs associated with inflammatory responses and autophagy. These findings suggested that probiotics ameliorated HFD-induced hepatic lipid accumulation in C. nasus by enhancing cholesterol metabolism and fatty acid oxidation, concomitantly with the suppression of fatty acid synthesis pathways. Additionally, probiotics protected against HFD-induced hepatic injury by enhancing antioxidant defenses and suppressing inflammation in C. nasus.

Hepatoprotective effects of polysaccharide from Morchella esculenta are associated with activation of the AMPK/Sirt1 signaling pathway in mice with NAFLD.

We examined the influence of dietary α-lipoic acid (LA; R enantiomer) supplementation in obese-complicated pregnancies on maternal postpartum body weight and metabolic health. Forty-eight female Sprague-Dawley rats were randomized into three dietary groups throughout pre-pregnancy, gestation, and lactation: (i) a low-calorie control diet (CON); (ii) a high calorie obesity-inducing diet (HC); or (iii) the HC diet with 0.25% LA (HC+LA). Following offspring weaning, all mothers were switched to the CON diet for a postpartum period of 140 days to assess maternal body weight and markers of metabolic health. HC-fed mothers showed excessive (p < 0.05) gestational weight gain (GWG), higher (p < 0.05) postpartum body weight, reduced (p < 0.05) glycemic control (lower glucose:insulin ratio) and higher (p = 0.06) hepatic cholesterol concentration versus CON mothers. In contrast, HC+LA mothers demonstrated lower (p < 0.05) body weight throughout the experimental period compared with HC mothers, primarily due to a marked reduction in GWG. Although LA did not protect (p > 0.05) against reduced glycemic control, it did alter several aspects of lipid metabolism including reduced serum HDL-C and a lower concentration of hepatic cholesterol which was mediated partly through a reduction in low-density lipoprotein receptor expression. We conclude that maternal obesity during pregnancy leads to a longer-term detrimental impact on weight gain and glycemic control, even after switching to a low-calorie postpartum diet. Maternal LA supplementation may be able to partially offset these effects, likely by protecting against excessive GWG during pregnancy. However, further work is required to determine the consequences of reduced serum HDL-C in LA-supplemented mothers.

Per- and polyfluoroalkyl substances (PFAS) are a large group of persistent chemicals that are pervasive in the environment leading to widespread exposure for humans. Perfluorooctanoic acid (PFOA), one of the most commonly measured PFAS in people, disrupts liver and serum lipid homeostasis as shown in animal toxicity and human epidemiological studies. We tested the hypothesis that the effects of PFOA exposure in mice expressing mouse PPARα (mPPARα) are driven largely through PPARα-dependent mechanisms while non-PPARα dependent mechanisms will be more apparent in mice expressing human PPARα (hPPARα). Female and male mPPARα, hPPARα, and PPARα null mice were exposed to PFOA (0.5, 1.4 or 6.2 mg PFOA/L) via drinking water for 14 weeks. Concurrently, mice consumed an American diet containing human diet-relevant amounts of fat and cholesterol. Here, we focused on the effects in female mice, given the dearth of data reported on PFAS-induced effects in females. Increasing the duration of PFOA exposure reduced weight gain in all genotypes of female mice while end-of-study body fat was lower in PFOA exposed hPPARα and PPARα null mice. Serum cholesterol, but not triacylglyceride, concentrations were increased by PFOA exposure in a PPARα-dependent manner. Hepatic triacylglycerides were higher in vehicle-exposed mPPARα and PPARα null mice than hPPARα mice, and PFOA significantly reduced concentrations in mPPARα and PPARα null mice only. In contrast, PFOA increased hepatic cholesterol content in a PPARα-dependent manner. Changes in liver and serum cholesterol may be explained by a strong, PPARα-dependent downregulation of Cyp7a1 expression. PFOA significantly increased PPARα target gene expression in mPPARα mice. Other nuclear receptors were examined: CAR target gene expression was only induced by PFOA in hPPARα and PPARα null mice. PXR target gene expression was induced by PFOA in all genotypes. Results were similar in male mice with two exceptions: (1) vehicle-exposed male mice of all genotypes were equally susceptible to diet-induced hepatic steatosis; (2) male mice drank less water, resulting in lower serum PFOA levels, which may explain the less significant changes in lipid endpoints. Overall, our results show that PFOA modifies triacylglyceride and cholesterol homeostasis independently and that PPARα plays an important role in PFOA-induced increases in liver and serum cholesterol.

This research investigated the effects of myricitrin on hypercholesterolemia and non-alcoholic fatty liver disease (NAFLD) in mice given a high-cholesterol diet (HCD). C57BL/6J mice were maintained for 20 weeks on an HCD with or without myricitrin. Myricitrin had no impact on the food consumption, body weight, or plasma triglyceride concentrations. However, myricitrin-supplemented mice had lower plasma total cholesterol (TC) concentrations and LDL + VLDL-cholesterol/TC proportion, and higher HDL-cholesterol/TC proportion than control mice, which resulted in a markedly decreased atherogenic index. Moreover, the levels of plasma C-reactive protein, oxidized LDL, lipoprotein(a), and plasminogen activator inhibitor-1, which are indicators for cardiovascular disease (CVD), were reduced, while levels of plasma paraoxonase, a cardioprotective enzyme, were greater in myricitrin-supplemented mice than in control mice. Myricitrin also meaningfully reduced liver weight and hepatic cholesterol content, and slightly alleviated fatty liver and fibrosis caused by an HCD. The plasma and hepatic cholesterol-lowering effects of myricitrin were partly associated with decreased activities of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase and acyl-CoA:cholesterol acyltransferase, which are involved in cholesterol synthesis and esterification, respectively, as well as mRNA expression. Myricitrin also altered other hepatic genes implicated in cholesterol homeostasis, including the downregulation of SREBP2 and ABCA1 mRNA expression and the upregulation of LDLR mRNA expression. Moreover, myricitrin decreased TBARS levels in the liver and erythrocytes by activating antioxidant enzymes (SOD and catalase). These results indicate that dietary myricitrin may offer therapeutic benefits for HCD-caused hypercholesterolemia and NAFLD, and may help reduce CVD risk.

The pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) is closely associated with increased oxidative stress and lipid peroxidation. Coenzyme Q (CoQ) and selenium (Se) are well-established antioxidants with protective effects against oxidative damage. This study aimed to investigate the effects of CoQ and Se in ameliorating MASH induced by a methionine choline-deficient (MCD) diet in mice. C57BL/6J male mice were fed either a methionine choline-sufficient (MCS) or MCD diet and treated with vehicle, CoQ (100 mg/kg), Se (158 μg/kg), or their combination (CoQ + Se) for 4 weeks. The MCD diet significantly increased hepatic steatosis, inflammation, and fibrosis compared to MCS controls. Treatment with CoQ and Se, particularly in combination, markedly reduced the MAFLD activity score, hepatic inflammation, and fibrosis. Combined supplementation of CoQ and Se significantly decreased serum alanine aminotransferase and aspartate aminotransferase levels and hepatic TG and cholesterol concentrations. CoQ and Se effectively mitigated hepatic oxidative stress by enhancing catalase and superoxide dismutase activities, increasing glutathione peroxidase (GPX) activity, and restoring the GSH/GSSG ratio. Lipid peroxidation markers, such as malondialdehyde and 4-hydroxynonenal, were significantly reduced. Furthermore, the expression of ferroptosis-related markers, including acyl-CoA synthetase long-chain family member 4, arachidonate 12-lipoxygenase, and hepatic non-heme iron content, was significantly downregulated, while GPX4 expression was upregulated by combined CoQ and Se treatment. CoQ and Se synergistically alleviate MASH progression by reducing oxidative stress and lipid peroxidation, which may contribute to the suppression of ferroptosis. Combined CoQ and Se supplementation demonstrates therapeutic potential for managing MASH and related liver injury.

To illustrate the effects of chitosan oligosaccharide (COS) supplementation on abdominal fat deposition (AFD), lipid metabolism, cecal microbiota composition, and short-chain fatty acids (SCFA) content in the ceca of broilers. Totally, 144 one-day-old male Arbor Acres broilers were randomly allocated into two groups with six replicates and 12 broilers per replicate. The control group (CON) was fed the basal diet; the treatment group was fed the basal diet with 200-mg/kg COS (COS200). COS supplementation led to a reduction (p < 0.05) in AFD, serum triglyceride, hepatic high-density lipoprotein cholesterol content, hepatic fatty acid synthase, acetyl-coenzyme A carboxylase gene expression level, and peroxisome proliferator-activated receptor γ gene expression level in abdominal fat (AF). Furthermore, COS supplementation resulted in higher (p < 0.05) relative abundance of cecal Bacteroidetes and Alistipes but lower (p < 0.05) relative abundance of Desulfobacterota, Patescibacteria, Campilobacterota, Deferribacterota, Shuttleworthia, and Erysipelatoclostridium, accompanied by increasing acetic acid, propionic acid, isobutyric acid, caproic acid, and total acid content. The AF weight inversely (p < 0.05) correlated with the relative abundance of Bacteroidota and isobutyric acid content. Overall, COS supplementation reduced AF deposition by inhibiting hepatic fatty acid synthesis, abdominal adipocyte differentiation, and proliferation-related gene expression, which was associated with the changes in cecal microbiota composition and SCFA content.

Excessive cholesterol levels can lead to hypercholesterolemia, which is related to cardiovascular diseases (CVDs), and CVDs are a serious threat to human health. Therefore, lowering cholesterol levels is necessary, and diet intervention is safer than drugs are. The cholesterol-lowering effect of Levilactobacillus brevis M-10 isolated from spontaneously fermented millet sour porridge was investigated in fifty C57BL/6N male mice. After a 4-week intervention, the food intake, weight gains and organ indices were calculated; the lipid contents in the serum, liver, and feces were determined; the histopathology of the liver tissues was observed; the expression of metabolism-related genes was determined; and short-chain fatty acid (SCFA) levels in the droppings were monitored. The results showed that administration of a high dose of L. brevis M-10 (1 × 1010CFU/mL) significantly reduced food intake, suppressed weight gain; prevented excessive liver growth; and reduced the total serum cholesterol, triglycerides, low-density lipoproteins; and total hepatic cholesterol and triglyceride contents (P < 0.05) in high-cholesterol mice. Moreover, a high dose of L. brevis M-10 significantly promoted the fecal excretion of cholesterol and triglycerides (P < 0.05) and alleviated liver damage induced by a high-cholesterol diet. Furthermore, a high dose of L. brevis M-10 significantly downregulated the cholesterol metabolism-related gene expression of NPC1L1, ACAT2, HMG-CoA, and SREBP2 but upregulated the gene expression of ABCG5, CYP7A1, and LXR-α (P < 0.05). Additionally, a high dose of L. brevis M-10 significantly increased SCFA contents, including those of acetic acid, propionic acid and n-butyric acid (P < 0.05). These findings could provide support for the use of L. brevis M-10 in the application of functional foods to alleviate hypercholesterolemia.