Excessive Lipid Accumulation Research Articles

Heightened cholesterol 25-hydroxylase expression in aged lung during Streptococcus pneumoniae

IntroductionAlveolar macrophages (AM) are critical effectors of the immune response and are essential for host responses to Streptococcus pneumoniae. Changes in lipid metabolism in AM can alter cellular function and biology. Impaired metabolism can contribute to excessive lipid accumulation and pro-inflammatory signaling. Our current study was designed to examine the role of cholesterol 25-hydroxylase (Ch25h), a redox enzyme that catalyzes the oxidation of cholesterol to 25-hydroxycholesterol (25-HC), in modulating AM responses in the aged lung during S. pneumoniae infection.MethodsTo observe the impact of aging on Ch25h expression in AM during infection, in vitro and in vivo murine models of S. pneumoniae were used.ResultsAt baseline and in response to infection, cholesterol metabolism significantly altered in aged AM, which corresponded with increased lipid droplet formation. In vitro, treatment of aged macrophages with Ch25 h-specific siRNA improved S. pneumoniae clearance and enhanced phagocytic receptor expression. In vivo siRNA targeting significantly reduced Ch25h expression in aged lungs and improved clinical parameters during S. pneumoniae infection. Reduction of Ch25h was associated with changes in phagocytosis and antibacterial signaling, correlated with changes in cholesterol metabolism, and increased S. pneumoniae clearance.DiscussionThe results of our current study demonstrate that Ch25h plays an essential role in modulating aged AM responses to S. pneumoniae.

Hsp90α promotes lipogenesis by stabilizing FASN and promoting FASN transcription via LXRα in hepatocellular carcinoma.

Excessive lipid accumulation promotes the occurrence and progression of hepatocellular carcinoma (HCC), accompanied by high levels of fatty acid synthetase (FASN) and more active lipogenesis. Heat shock protein 90 (Hsp90) acts as a chaperone to maintain the stability and activity of the client proteins. Studies have revealed that Hsp90 regulates the lipid metabolism of HCC, but the effect of Hsp90 on FASN still remains unknown. This study aims to discover the mechanism of Hsp90 inhibition on lipid accumulation and investigate the different effects of Hsp90 N-terminal domain inhibitor STA9090 and C-terminal domain inhibitor novobiocin (NB) on FASN protein stability and transcription pathway in HCC. We found that HCC cells tended to store lipids, which could be disrupted by Hsp90 inhibitors in vivo and in vitro. High levels of Hsp90α and FASN in tumor tissue had correlation with poor prognosis of HCC patients and Hsp90α interacted with FASN to maintain its protein stability. Furthermore, N-terminal domain of Hsp90α was essential for process of sterol regulatory element binding protein 1 (SREBP1) to activate FASN transcription and Hsp90α prevented proteasomal degradation of liver X receptor α (LXRα) to upregulate FASN transcription via LXRα/SREBP1 axis. Our data reveals that Hsp90α promotes lipid accumulation by increasing the protein stability and FASN mRNA transcription, and can be alleviated by Hsp90 inhibitors, which provides a theoretical basis for Hsp90-targeted therapy on lipid metabolism in HCC.

Andrographolide prevents renal fibrosis via decelerating lipotoxicity-mediated premature senescence of tubular epithelial cells

Excessive lipid accumulation often occurs in the early stage of chronic kidney disease (CKD) which is prone to induce oxidative stress and mitochondrial damage, promoting the progression of kidney fibrosis. Andrographolide (AP), a multifunctional natural terpenoids derived from Andrographis paniculate, has been suggested to play beneficial roles in metabolic disorders-associated disease. Here, we reported that AP effectively counteracts tubule injury and interstitial fibrosis in mice fed with a long-term high-fat diet (HFD). AP treatment decreased HFD-induced lipid accumulation in kidney parenchyma and attenuated lipotoxicity-mediated oxidative stress and mitochondrial dysfunction, resulting in a marked decrease in of tubular cell senescence. Importantly, AP inhibited senescence-associated secretory phenotype (SASP) secretion by senescent tubular cells, and in turn suppressed proliferation and activation of fibroblasts in a paracrine effect. Furthermore, we revealed that AP functions as an AMP-activated protein kinase (AMPK) activator to ameliorate renal lipid accumulation through coordinately modulating AMP-activated protein kinase AMPK target genes. By stimulation of AMPK activity, AP protects injured kidney against tubular cell senescence and fibroblast activation. These results suggest the potential therapeutic application of AP in the prevention and treatment of CKD, highlighting the promising drug strategy of targeting the lipotoxicity-mediated premature senescence in tubular cells.

Impeding Nucleotide-Binding Oligomerization Domain-Like Receptor 3 Inflammasome Ameliorates Cardiac Remodeling and Dysfunction in Obesity-Associated Cardiomyopathy.

Inflammation and metabolic disturbances are key culprits in the pathogenesis of obesity-associated cardiomyopathy. The NLRP3 (nucleotide-binding oligomerization domain-like receptor 3) inflammasome mediates the release of the proinflammatory cytokines IL-1β (interleukin-1β) and IL-18 by activating caspase-1, which is strongly implicated in metabolic disturbances. We here sought to determine whether NLRP3 inflammasome inhibition could ameliorate obesity cardiomyopathy and if so, to further explore its underlying mechanisms. Male mice were fed a high-fat diet for 24 weeks to induce obesity cardiomyopathy. MCC950 was used to inhibit NLRP3 inflammasome activation. Recombinant adeno-associated virus serotype 9 encoding TXNIP (thioredoxin-interacting protein) under cTnT (cardiac troponin T) promoter and the mitochondrial-targeted antioxidant MitoTEMPO were injected into obese mice to investigate the specific mechanism. To mimic obesity cardiomyopathy invitro, neonatal rat ventricular myocytes transfected with the small interfering RNA against TXNIP were incubated with 400 μmol palmitic acid for 24 hours. NLRP3 inflammasome was significantly increased in obese hearts. NLRP3 inflammasome inhibition by NLRP3 deletion or MCC950 prevented obesity-induced cardiac systolic and diastolic dysfunction, myocardial hypertrophy and fibrosis, and excessive lipid accumulation in male mice. Conversely, TXNIP overexpression worsened obesity-associated cardiomyopathy. Similarly, MCC950 treatment or TXNIP knockdown reduced palmitic acid-induced NLRP3 inflammasome activation and lipid storage. Mechanistically, abnormal NF-κB (nuclear factor kappa B) pathway activation, increased mitochondrial reactive oxygen species, and elevated TXNIP levels led to excessive NLRP3 inflammasome activation. Our study confirms that aberrant NLRP3 inflammasome activation in cardiomyocytes worsens obesity-associated cardiomyopathy and implicates inhibition of NLRP3 inflammasome as a potent therapeutic approach for obesity cardiomyopathy.

Carbon dots induce endoplasmic reticulum stress-mediated lipid dysregulation and embryonic developmental toxicity in zebrafish

Carbon dots (CDs) are widely utilized due to their exceptional physical and chemical properties. Nevertheless, there is a paucity of research examining the potential toxicity of carbon dots to human health, particularly with regard to developmental toxicity. The present study demonstrated that exposure to CDs resulted in increased mortality and malformations in zebrafish embryos. Further bioinformatics analyses indicated that CDs-induced lipid metabolism disorders may represent a significant pathway for developmental toxicity in zebrafish embryos. This can result in aberrant expression of genes involved in lipid metabolism, which ultimately leads to endoplasmic reticulum stress (ERS)-induced accumulation of excess lipids in the body. It can therefore be surmised that exposure to CDs in early life ultimately leads to developmental toxicity by inducing ERS-induced lipid metabolism disorders. The findings of this study suggest that there is a risk of long-term exposure to CDs from early life, and provide a theoretical basis and data support for the prevention of potential hazards of CDs.

Silk Fibroin Nanoparticles as a Drug Delivery System of 3,3'-Diindolylmethane with Potential Antiobesogenic Activity.

Obesity is a global disease characterized by excessive lipid accumulation in the adipose tissue. There is an urgent need to explore alternative compounds to treat obesity. Low-molecular-weight compounds from plants, like 3,3'-diindolylmethane (DIM), are emerging as potential alternatives for obesity treatment. In this work, DIM is encapsulated into silk fibroin nanoparticles (SFNP) to evaluate the antiobesogenic potential. The obtained spherical-like SFNPs have a particle size between 165 and 200 nm, a polydispersity index between 0.11 and 0.15, and a zeta potential from -27 to -37 mV. DIM does not modify the nanoparticle shape but changes the secondary structure of fibroin and generates smaller nanoparticles (145 nm). DIM-loaded SFNP (SFNP-DIM) enhance their antioxidant capacity by 4.4-fold compared to SFNP. SFNP-DIM does not show cytotoxicity on white-like adipocytes, unlike 3T3-L1 preadipocytes, where cell viability decreased in a concentration-dependent manner. The SFNP-DIM treatment (5 μM, 0.03 mg SFNP mL-1) does not modify the morphology of white-like adipocytes. It produces an apparent augmentation in the size and number of intracellular lipid droplets and increases by 2.18 ± 0.4-fold of triglyceride content. These findings demonstrated that SFNPs could be a potential delivery system of DIM, suggesting a potential therapeutic agent for treating obesity.

The Protective Role of miR-130b-3p Against Palmitate-Induced Lipotoxicity in Cardiomyocytes Through PPARγ Pathway.

Excess lipid accumulation in the heart is associated with lipotoxicity and cardiac dysfunction due to excessive fatty acid oxidation. Peroxisome proliferator-activated receptor gamma (PPARγ) modulates the expression of key molecules involved in the FA metabolic pathway. Cardiomyocyte-specific overexpression of PPARγ causes dilated cardiomyopathy associated with lipotoxicity in mice. miR-130b-3p has been shown to be downregulated in the plasma of idiopathic dilated cardiomyopathy patients, but its role in modulating cardiomyocyte lipotoxicity via PPARγ remains unclear. Our objective was to investigate the protective role of miR-130b-3p against palmitate-induced lipotoxicity in cardiomyocytes through the modulation of the PPARγ signaling pathway. Human cardiomyoblasts were treated with palmitate. Intracellular lipid accumulation and expression of PPARγ and its downstream targets (CD36, FABP3, CAV1, VLDLR) were analyzed. Mitochondrial oxidative stress was assessed via MitoTracker Green and Redox Sensor Red staining and expression of CPT1B and SOD2. Endoplasmic reticulum stress and apoptosis were determined by examining GRP78, ATF6, XBP1s, CHOP, and caspase-3 expression. miR-130b-3p overexpression was achieved using transfection methods, and its effect on these parameters was evaluated. Luciferase assays were used to confirm PPARγ as a direct target of miR-130b-3p. Palmitate treatment led to increased lipid accumulation and upregulation of PPARγ and its downstream targets in human cardiomyoblasts. Palmitate also increased mitochondrial oxidative stress, endoplasmic reticulum stress and apoptosis. miR-130b-3p overexpression reduced PPARγ expression and its downstream signaling, alleviated mitochondrial oxidative stress and decreased endoplasmic reticulum stress and apoptosis in palmitate-stimulated cardiomyoblasts. Luciferase assays confirmed PPARγ as a direct target of miR-130b-3p. Our findings suggest that miR-130b-3p plays a protective role against palmitate-induced lipotoxicity in cardiomyocytes by modulating the PPARγ signaling pathway.

Exploring the impact of lipid stress on sperm cytoskeleton: insights and prospects.

The decline in male fertility correlates with the global rise in obesity and dyslipidaemia, representing significant public health challenges. High-fat diets induce metabolic alterations, including hypercholesterolaemia, hepatic steatosis and atherosclerosis, with detrimental effects on testicular function. Testicular tissue, critically dependent on lipids for steroidogenesis, is particularly vulnerable to these metabolic disruptions. Excessive lipid accumulation within the testes, including cholesterol, triglycerides and specific fatty acids, disrupts essential sperm production processes such as membrane formation, maturation, energy metabolism and cell signalling. This leads to apoptosis, impaired spermatogenesis, and abnormal sperm morphology and function, ultimately compromising male fertility. During spermiogenesis, round spermatids undergo extensive reorganization, including the formation of the acrosome, manchette and specialized filamentous structures, which are essential for defining the final sperm cell shape. In this Perspective, we examine the impact of high-fat diets on the cytoskeleton of spermatogenic cells and its consequences to identify the mechanisms underlying male infertility associated with dyslipidaemia. Understanding these processes may facilitate the development of therapeutic strategies, such as dietary interventions or natural product supplementation, that aim to address infertility in men with obesity and hypercholesterolaemia. The investigation of cytoskeleton response to lipid stress extends beyond male reproduction, offering insights with broader implications.

Pea Albumin Alleviates Oleic Acid-Induced Lipid Accumulation in LO2 Cells Through Modulating Lipid Metabolism and Fatty Acid Oxidation Pathways.

Excessive lipid accumulation in the liver can cause NAFLD, leading to chronic liver injury. To relieve liver lipid accumulation by dietary proteins, this study used oleic acid (OA) induction to establish a stable in vitro LO2 cell lipid accumulation model. This model was used to explore the mechanism by which pea albumin (PA) regulates lipid levels in LO2 cells. PA has been shown to ameliorate OA-induced lipid accumulation in LO2 cells by reducing the aggregation of intracellular lipid droplets and lowering cell TG and TC levels. In addition, it can alleviate OA-induced LO2 cell damage and oxidative stress, reduce cellular ALT and AST secretion, lower cellular MDA levels, and increase GSH-Px viability. Regulation of lipid metabolism in LO2 cells involves inhibiting the cellular lipid synthesis pathway and activating the expression of proteins related to the triglyceride catabolic and fatty acid oxidation pathways. PA contributes to regulating lipid accumulation in LO2 cells. This study provides new insights into alleviating liver fat accumulation and a theoretical basis for exploring the mechanism of protein regulation of liver cell lipid metabolism.

Evaluation of Rosmarinic Acid Attenuation Effect on Endoplasmic Reticulum Stress in Swiss-type Mice Affected With Nonalcoholic Steatohepatiti

Background and Objectives: Nonalcoholic steatohepatitis is a severe liver disease characterized by excess lipid accumulation (steatosis) and inflammation in the liver. Endoplasmic reticulum stress is considered one of the crucial factors in nonalcoholic steatohepatitis pathophysiology. Rosmarinic acid is a herbal medicine with antioxidant and anti-inflammatory properties. This study aimed to evaluate the effect of rosmarinic acid on reducing the endoplasmic reticulum stress induced by nonalcoholic steatohepatitis in male Swiss-type mice. Methods: The study animals were grouped into four: Saline, rosmarinic acid, nonalcoholic steatohepatitis, and nonalcoholic steatohepatitis-rosmarinic acid. Nonalcoholic steatohepatitis was induced by a diet without methionine-choline for 8 weeks, and rosmarinic acid was injected intraperitoneally daily for 8 weeks in mice. After 8 weeks, the animals were killed, and their liver samples were obtained. Real-time PCR was used for molecular studies. Data analyses were performed by one-way analysis of variance and Tukey's post hoc test. Results: Findings of this study showed that rosmarinic acid alleviated mRNA levels of GRP78, IRE-1, and PERK while increasing the Apo B expression. Conclusion: The results suggest that rosmarinic acid ameliorates endoplasmic reticulum stress parameters, upregulates Apo B expression as a key factor in triglyceride exit from the liver, and thereby improves nonalcoholic steatohepatitis in male Swiss-type mice.

Altered drug metabolism and increased susceptibility to fatty liver disease in a mouse model of myotonic dystrophy

Myotonic Dystrophy type 1 (DM1), a highly prevalent form of muscular dystrophy, is caused by (CTG)n repeat expansion in the DMPK gene. Much of DM1 research has focused on the effects within the muscle and neurological tissues; however, DM1 patients also suffer from various metabolic and liver dysfunctions such as increased susceptibility to metabolic dysfunction-associated fatty liver disease (MAFLD) and heightened sensitivity to certain drugs. Here, we generated a liver-specific DM1 mouse model that reproduces molecular and pathological features of the disease, including susceptibility to MAFLD and reduced capacity to metabolize specific analgesics and muscle relaxants. Expression of CUG-expanded (CUG)exp repeat RNA within hepatocytes sequestered muscleblind-like proteins and triggered widespread gene expression and RNA processing defects. Mechanistically, we demonstrate that increased expression and alternative splicing of acetyl-CoA carboxylase 1 drives excessive lipid accumulation in DM1 livers, which is exacerbated by high-fat, high-sugar diets. Together, these findings reveal that (CUG)exp RNA toxicity disrupts normal hepatic functions, predisposing DM1 livers to injury, MAFLD, and drug clearance pathologies that may jeopardize the health of affected individuals and complicate their treatment.

NPRC promotes hepatic steatosis via USP30-mediated deubiquitination of C/EBPβ

Background and aimsMetabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent chronic liver condition characterised by dysregulated lipid metabolism. The role of Natriuretic Peptide Receptor C (NPRC), a receptor responsible for clearing natriuretic peptides, in MAFLD remains elusive. Therefore, the aim of the present study was to elucidate the role of NPRC in MAFLD progression. Approach and resultsThis study demonstrated that NPRC enhanced lipid metabolism reprogramming and accelerated MAFLD progression. Mechanistic investigations, including proteomic and ubiquitination analyses, revealed that elevated NPRC levels stabilized the C/EBPβ protein, leading to excessive lipid accumulation. The DNA-binding domain (DBD) of C/EBPβ interacted with the deubiquitinase USP30, a key regulator that inhibited K149-specific K48-linked polyubiquitination of C/EBPβ. Importantly, the ANPR region of NPRC bound to USP30, facilitating the deubiquitination of C/EBPβ. Furthermore, virtual screening identified punicalin, a natural compound, as a potential inhibitor of NPRC expression, which may reduce hepatic lipid accumulation, inflammation and fibrosis. ConclusionsOur findings indicate that NPRC recruits USP30 to mediate the deubiquitination of C/EBPβ, driving lipid metabolism reprogramming. Targeting NPRC could represent a promising therapeutic approach for MAFLD.

Impacts of time-restricted feeding on middle-aged and old mice with obesity.

Time-restricted feeding is known to ameliorate obesity in young mice. However, evaluation of its effect in old age is still lacking. The current work aims to investigate the effects of time-restricted feeding on treating pre-existing obesity in old animals. The study utilized middle-aged and old high fat diet-induced obese mice and subjected them to 8h daily time-restricted feeding. Aged obese mice did not lose fat mass but lost lean mass after 8 weeks of treatment. In addition, time-restricted feeding reduced adiposity in brown adipose tissue, reversed excessive hepatic lipid accumulation, and improved glucose homeostasis in middle-aged and old obese mice. Mechanistic studies show that these metabolic benefits were mediated by transcriptional downregulation of essential genes responsible for hepatic adipogenesis and adipose tissue chronic inflammation. These results demonstrate that time-restricted feeding improves metabolic health and has beneficial effects in combating diet-induced obesity in aged obese mice. KEY POINTS: Contrary to in young obese mice, in old obese mice time-restricted feeding did not significantly reduce body fat but decreased lean mass. Time-restricted feeding reduced adipose tissue inflammation, reversed fatty liver, and improved glucose homeostasis in aged mice with diet-induced obesity. Time-restricted feeding is effective in improving metabolic homeostasis in aged mice, but less effective in terms of reducing obesity. Future studies should investigate the underlying mechanism of how ageing impaired intermittent fasting induced fat loss.

Different time-restricted feeding patterns potentially modulate metabolic health by altering tryptophan metabolism of gut microbes in pigs

Time-restricted feeding has emerged as a preferred approach for alleviating metabolic disorders, but the potential microbiological mechanism remains poorly understood. This study used a growing pig model to mimic common-sense eating habits. Four feeding patterns were set up, including ad libitum feeding (ALF) for daily irregulated eating habits, time-restricted feeding (TRF) for three meals a day, early time-restricted feeding (eTRF) for skipping dinner and mid-day time-restricted feeding (mTRF) for skipping breakfast. The results showed that the three time-restricted feeding patterns (TRF, eTRF and mTRF) resulted in a reduction of hepatic fat accumulation and a decrease in hepatic function markers compared to the ALF pattern. However, this was independent of food consumption. Transcriptome analysis of the liver showed that the three time-restricted feeding patterns downregulated the expression of genes related to gluconeogenesis, β-oxidation, lipid accumulation, and urea cycle, and upregulated the expression of genes related to lipogenesis and glycolysis compared to the ALF pattern. Microbiome and metabolome analyses showed that Lactobacillus enriched in the colon of pigs in three time-restricted groups were negatively correlated with serum triglyceride. Meanwhile, three time-restricted feeding patterns elevated the levels of the microbial metabolite indole-3-lactic acid, which was further confirmed to reduce excessive hepatic lipid accumulation in vitro. Overall, time-restricted feeding potentially improved metabolic health by modulating gut microbiota and metabolites.

Activity and phosphatidylcholine transfer protein interactions of skeletal muscle thioesterase Them2 enable hepatic steatosis and insulin resistance

Thioesterase superfamily member 2 (Them2), a long-chain fatty acyl-CoA thioesterase that is highly expressed in oxidative tissues, interacts with phosphatidylcholine transfer protein (PC-TP) to regulate hepatic lipid and glucose metabolism and to suppress insulin signaling. High-fat diet (HFD)-fed mice lacking Them2 globally or specifically in skeletal muscle, but not liver, exhibit reduced hepatic steatosis and insulin resistance. Here, we report that the capacity of Them2 in skeletal muscle to promote hepatic steatosis and insulin resistance depends on both its catalytic activity and interaction with PC-TP. Two residues of Them2 catalytic site were mutated (N50A/D65A) to produce the inactive enzyme while maintaining its homotetrameric structure and interaction with PC-TP. Restoration of skeletal muscle expression in Them2-/- mice using recombinant adeno-associated virus revealed that wild-type (WT), but not N50A/D65A Them2, promoted HFD-induced weight gain and hepatic steatosis. This was accompanied by greater impairment of insulin sensitivity in WT compared with N50A/D65A Them2. Pharmacological inhibition or genetic ablation of PC-TP attenuated these effects. In reductionist experiments, conditioned medium collected from WT primary cultured myotubes promoted excess lipid accumulation in oleic acid-treated primary cultured hepatocytes relative to Them2-/- myotubes, which was attributable to secreted extracellular vesicles (EV). Reconstitution of Them2 expression in Them2-/- myotubes affirmed the requirements for catalytic activity and PC-TP interactions for EV to promote lipid accumulation in hepatocytes. These studies provide valuable mechanistic insights whereby Them2 in skeletal muscle promotes hepatic steatosis and establish both Them2 and PC-TP as represent attractive targets for managing metabolic dysfunction-associated steatotic liver disease.

Distribution of lipid droplets in hippocampal neurons and microglia: impact of diabetes and exercise.

Neuroinflammation, aging, and neurodegenerative disorders are associated with excessive accumulation of neutral lipids in lipid droplets (LDs) in microglia. Type 2 diabetes mellitus (T2DM) may cause neuroinflammation and is a risk factor for neurodegenerative disorders. Here, we show that hippocampal pyramidal neurons contain smaller, more abundant LDs than their neighboring microglia. The density of LDs varied between pyramidal cells in adjacent subregions, with CA3 neurons containing more LDs than CA1 neurons. Within the CA3 region, a gradual increase in the LD content along the pyramidal layer from the hilus toward CA2 was observed. Interestingly, the high neuronal LD content correlated with less ramified microglial morphotypes. Using the db/db model of T2DM, we demonstrated that diabetes increased the number of LDs per microglial cell without affecting the neuronal LD density. High-intensity interval exercise induced smaller changes in the number of LDs in microglia but was not sufficient to counteract the diabetes-induced changes in LD accumulation. The changes observed in response to T2DM may contribute to the cerebral effects of T2DM and provide a mechanistic link between T2DM and neurodegenerative disorders.

Targeting ketone body metabolism to treat fatty liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a metabolic disorder marked by excessive accumulation of lipids within the liver. If untreated, this condition can progress to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and ultimately, hepatocellular carcinoma (HCC). Given the liver's pivotal role in glucose and fatty acid metabolism, disruptions in these processes are commonly observed in MASLD. Ketone bodies, crucial energy metabolites primarily produced in the liver, are also closely related to the progression of MASLD. Recent studies have demonstrated that disrupted ketogenesis not only accompanies MASLD, but may also play a causal role in its development and progression. Moreover, activation of the ketogenic pathway has been suggested as a promising strategy for reducing excessive hepatic fat accumulation. This review focuses on the regulation of ketogenesis in MASLD, emphasizing the significance of dietary and pharmacological interventions as potential therapeutic approaches to treat fatty liver disease.

Expression of TWEAK/Fn14 axis in the context of metabolic dysfunction associated-fatty liver disease: an approach in liver regeneration

Background: One of the pathways involved in liver regeneration processes is TWEAK/Fn14 (tumor necrosis factor-related weak inducer of apoptosis/fibroblast growth factor-inducible 14), which has been proposed to act directly and selectively on hepatic progenitor cells; however, its role in the regeneration of steatotic liver metabolic dysfunction associated fatty liver disease has not been fully elucidated. Objective: To evaluate the behavior of Fn14 and its ligand TWEAK, as well as cellular stress signals as biochemical cues for possible liver regeneration in MAFLD. Materials and methods: A prospective study was carried out where the behavior of Fn14 and its ligand TWEAK, as well as cellular stress signals were observed as biochemical indications of a possible liver regeneration in a condition of tissue damage caused by excessive lipid accumulation. The expression of TWEAK, Fn14 and heat shock proteins in hepatic steatosis of non-alcoholic origin was assessed using immunohistochemistry and western blotting. Results: The histological classification of the tissues under study corresponded to microvesicular steatosis. We report a high level of expression of heat shock proteins in the cytoplasm. The expression of TWEAK and Fn14 in liver tissue affected by lipid accumulation was localized in the cytoplasm of hepatocytes, showing a higher intensity of reactivity for Fn14 compared to its ligand TWEAK. Conclusion: The expression of TWEAK/Fn14 axis was positive suggesting reactivity of the signaling pathway in metabolic dysfunction associated fatty liver disease.

Leveraging adrenergic receptor blockade for enhanced nonalcoholic fatty liver disease treatment via a biomimetic nanoplatform

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation, steatosis and fibrosis. Sympathetic nerves play a critical role in maintaining hepatic lipid homeostasis and regulating fibrotic progression through adrenergic receptors expressed by hepatocytes and hepatic stellate cells; however, the use of sympathetic nerve-focused strategies for the treatment of NAFLD is still in the infancy. Herein, a biomimetic nanoplatform with ROS-responsive and ROS-scavenging properties was developed for the codelivery of retinoic acid (RA) and the adrenoceptor antagonist labetalol (LA). The nanoplatform exhibited improved accumulation and sufficient drug release in the fibrotic liver, thereby achieving precise codelivery of drugs. Integration of adrenergic blockade effectively interrupted the vicious cycle of sympathetic nerves with hepatic stellate cells (HSCs) and hepatocytes, which not only combined with RA to restore HSCs to a quiescent state but also helped to reduce hepatic lipid accumulation. We demonstrated the excellent ability of the biomimetic nanoplatform to ameliorate liver inflammation, fibrosis and steatosis. Our work highlights the tremendous potential of a sympathetic nerve-focused strategy for the management of NAFLD and provides a promising nanoplatform for the treatment of NAFLD.

Aged garlic oligosaccharides modulate host metabolism and gut microbiota to alleviate high-fat and high-cholesterol diet-induced atherosclerosis in ApoE−/− mice

Atherosclerosis (AS) is a cardiovascular disease caused by excessive accumulation of lipids in arterial walls. In this study, we developed an AS model in ApoE−/− mice using a high-fat, high-cholesterol diet and investigated the anti-AS mechanism of aged garlic oligosaccharides (AGOs) by focusing on the gut microbiota. Results revealed that AGOs exhibited significant anti-AS effects, reduced trimethylamine N-oxide levels from 349.9 to 189.2 ng/mL, and reduced aortic lipid deposition from 31.7 % to 9.5 %. AGOs significantly increased the levels of short-chain fatty acids in feces, in which acetic, propionic, and butyric acids were increased from 1.580, 0.364, and 0.469 mg/g to 2.233, 0.774, and 0.881 mg/g, respectively. An analysis of the gut microbiota indicated that AGOs restored alpha and beta diversity, decreased the Firmicutes/Bacteroidetes ratio, and promoted the dominance of the genus Akkermansia. A metagenomic analysis revealed that AGOs alleviated AS through the ABC transporter pathway and the lipopolysaccharide biosynthesis pathway.