Diet-induced Hepatic Steatosis Research Articles

Dietary medium-chain fatty acids reduce hepatic fat accumulation via activation of a CREBH-FGF21 axis

ObjectiveDietary medium-chain fatty acids (MCFAs), characterized by chain lengths of 8–12 carbon atoms, have been proposed to have beneficial effects on glucose and lipid metabolism, yet the underlying mechanisms remain elusive. We hypothesized that MCFA intake benefits metabolic health by inducing the release of hormone-like factors. MethodsThe effects of chow diet, high-fat diet rich in long-chain fatty acids (LCFA HFD) fed ad libitum or pair-fed to a high-fat diet rich in MCFA (MCFA HFD) on glycemia, hepatic gene expression, circulating fibroblast growth factor 21 (FGF21), and liver fat content in both wildtype and Fgf21 knockout mice were investigated. The impact of a single oral dose of an MCFA-rich oil on circulating FGF21 and hepatic Fgf21 mRNA expression was assessed. In flag-tagged Crebh knockin mice and liver-specific Crebh knockout mice, fed LCFA HFD or MCFA HFD, active hepatic CREBH and hepatic Fgf21 mRNA abundance were determined, respectively. ResultsMCFA HFD improves glucose tolerance, enhances glucose clearance into brown adipose tissue, and prevents high-fat diet-induced hepatic steatosis in wildtype mice. These benefits are associated with increased liver expression of CREBH target genes (Apoa4 and Apoc2), including Fgf21. Both acute and chronic intake of dietary MCFAs elevate circulating FGF21. Augmented hepatic Fgf21 mRNA following MCFA HFD intake is accompanied by higher levels of active hepatic CREBH; and MCFA-induced hepatic Fgf21 expression is blocked in mice lacking Crebh. Notably, while feeding male and female Fgf21 wildtype mice MCFA HFD results in reduced liver triacylglycerol (TG) levels, this liver TG-lowering effect is blunted in Fgf21 knockout mice fed MCFA HFD. The reduction in liver TG levels observed with MCFA HFD was independent of weight loss. ConclusionsDietary MCFAs reduce liver fat accumulation via activation of a CREBH-FGF21 signaling axis.

Hepatic IL22RA1 deficiency promotes hepatic steatosis by modulating oxysterol in the liver.

Imbalance in lipid metabolism is the main cause of nonalcoholic fatty liver disease (NAFLD). While the pathogenesis of lipid accumulation mediated by extrahepatic regulators has been extensively studied, the intrahepatic regulators modulating lipid homeostasis remain unclear. Previous studies have shown that systemic administration of interleukin-22 (IL-22) protects against NAFLD; however, the role of IL-22/IL22RA1 signaling in modulating hepatic lipid metabolism remains uncertain. This study shows hepatic IL22RA1 is vital in hepatic lipid regulation. IL22RA1 is downregulated in palmitic acid-treated mouse primary hepatocytes, as well as in the livers of NAFLD model mice and patients. Hepatocyte-specific Il22ra1 knockout (HKO) mice display diet-induced hepatic steatosis, insulin resistance, impaired glucose tolerance, increased inflammation, and fibrosis compared with flox/flox mice. This is attributed to increased lipogenesis mediated by the accumulation of hepatic oxysterols, particularly, 3 beta-hydroxy-5-cholestenoic acid (3β HCA). Mechanistically, hepatic IL22RA1 deficiency facilitates 3β HCA deposition via the activating transcription factor 3 (ATF3)/oxysterol 7 alpha-hydroxylase (CYP7B1) axis. Notably, 3β HCA facilitates lipogenesis in MPHs and human liver organoids (HLOs) by activating LXR-alpha signaling, but IL-22 treatment attenuates this effect. Additionally, restoring CYP7B1 or silencing hepatic ATF3 reduces both hepatic 3β HCA and lipid contents in HKO mice. These findings indicate that IL22RA1 plays a crucial role in maintaining hepatic lipid homeostasis in an ATF3/CYP7B1-dependent manner, and establish a link between 3β HCA and hepatic lipid homeostasis.

Gut microbiota-mediated modulation of lipid metabolism by punicic acid in diet-induced hepatic steatosis

Gut microbiota-mediated modulation of lipid metabolism by punicic acid in diet-induced hepatic steatosis

CD9 Counteracts Liver Steatosis and Mediates GCGR Agonist Hepatic Effects.

Glucagon receptor (GCGR) agonism offers potentially greater effects on the mitigation of hepatic steatosis. However, its underlying mechanism is not fully understood. Here, it screened tetraspanin CD9 might medicate hepatic effects of GCGR agonist. CD9 is decreased in the fatty livers of patients and upregulated upon GCGR activation. Deficiency of CD9 in the liver exacerbated diet-induced hepatic steatosis via complement factor D (CFD) regulated fatty acid metabolism. Specifically, CD9 modulated hepatic fatty acid synthesis and oxidation genes through regulating CFD expression via the ubiquitination-proteasomal degradation of FLI1. In addition, CD9 influenced body weight by modulating lipogenesis and thermogenesis of adipose tissue through CFD. Moreover, CD9 reinforcement in the liver alleviated hepatic steatosis, and blockage of CD9 abolished the remission of hepatic steatosis induced by cotadutide treatment. Thus, CD9 medicates the hepatic beneficial effects of GCGR signaling, and may server as a promising therapeutic target for hepatic steatosis.

Integration of Lipidomics and Transcriptomics Identifies the Regulation of Lipid Homeostasis as Potential Mechanisms of Konjac Glucomannan against Hepatic Steatosis.

Hepatic steatosis is characterized by substantial disruption in the liver's lipid level regulation. Konjac glucomannan (KGM) is acknowledged as a nutritious food that has the potential to prevent hyperlipidemia. This study utilized lipidomics and transcriptomics to investigate the efficacy of KGM in alleviating high-fat diet-induced hepatic steatosis by regulating lipid homeostasis. The findings indicated that supplementation of KGM for a duration of 10 weeks led to significant decreases in body weight, liver weight, and epididymal fat tissue weight. Furthermore, improvements in lipid concentrations in plasma and liver samples were observed, along with enhancements in glucose tolerance and the mitigation of liver damage. Additionally, lipidomics analysis revealed that the primary differential lipid metabolites were mainly associated with fatty acid metabolism pathways. Transcriptomic analysis showed that KGM significantly altered the gene expression of the peroxisome proliferator-activated receptor (PPAR) signaling pathway in the liver. Moreover, KGM demonstrated a significant regulatory impact on the hepatic expression of PPARγ, potentially mitigating hepatic steatosis through modulation of the PPARγ-mediated lipid metabolism pathway. In conclusion, these findings suggest that KGM effectively mitigates steatosis by modulating hepatic lipid metabolites and controlling PPARγ-mediated genes in the liver.

Nobiletin Protects Against Alcoholic Liver Disease in Mice via the BMAL1-AKT-Lipogenesis Pathway.

Alcoholic liver disease (ALD) is a global public health concern. Nobiletin, a polymethoxyflavone abundant in citrus fruits, enhances circadian rhythms and ameliorates diet-induced hepatic steatosis, but its influences on ALD are unknown. This study investigates the role of brain and muscle Arnt-like protein-1 (Bmal1), a key regulator of the circadian clock, in nobiletin-alleviated ALD. This study uses chronic ethanol feeding plus an ethanol binge to establish ALD models in Bmal1flox/flox and Bmal1 liver-specific knockout (Bmal1LKO) mice. Nobiletin mitigates ethanol-induced liver injury (alanine aminotransferase [ALT]), glucose intolerance, hepatic apoptosis, and lipid deposition (triglyceride [TG], total cholesterol [TC]) in Bmal1flox/flox mice. Nobiletin fails to modulated liver injury (ALT, aspartate aminotransferase [AST]), apoptosis, and TG accumulation in Bmal1LKO mice. The expression of lipogenic genes (acetyl-CoA carboxylase alpha [Acaca], fatty acid synthase [Fasn]) and fatty acid oxidative genes (carnitine pamitoyltransferase [Cpt1a], cytochrome P450, family 4, subfamily a, polypeptide 10 [Cyp4a10], and cytochrome P450, family4, subfamily a, polypeptide 14 [Cyp4a14]) is inhibited, andthe expression of proapoptotic genes (Bcl2 inteacting mediator of cell death [Bim]) is enhanced by ethanol in Bmal1flox/flox mice. Nobiletin antagonizes the expression of these genes in Bmal1flox/flox mice and not in Bmal1LKO mice. Nobiletin activates protein kinase B (PKB, also known as AKT)phosphorylation, increases the levels of the carbohydrate response element binding protein (ChREBP), ACC1, and FASN, and reduces the level of sterol-regulatory element binding protein 1 (SREBP1)and phosphorylation of ACC1 in a Bmal1-dependent manner. Nobiletin alleviates ALD by increasing the expression of genes involved in fatty acid oxidation by increasing AKT phosphorylation and lipogenesis in a Bmal1-dependent manner.

Hepatic miR-149-5p upregulation fosters steatosis, inflammation and fibrosis development in mice and in human liver organoids

Background & aimsThe incidence of metabolic dysfunction – associated steatotic liver disease (MASLD) is increasing worldwide. Alterations of hepatic microRNA (miRNA) expression/activity significantly contribute to the development and progression of MASLD. Genetic polymorphisms of miR-149 are associated with an increased susceptibility to develop MASLD in humans. Aberrant expression of miR-149 was also associated with metabolic alterations in several organs, but the impact of hepatic miR-149-5p deregulation in MASLD remains poorly characterized. MethodsMiR-149-5p was downregulated in the liver of mice by in vivo transduction with hepatotropic adeno-associated virus 8 (AAV8) harboring shRNAs specific for miR-149-5p (shmiR149) or scrambled shRNAs (shCTL). MASLD was then induced in mice with a methionine/ choline deficient (MCD, n=7 per group) or a fructose, palmitate and cholesterol-enriched (FPC, n=8-12 per group, per protocol) diet. The impact of miR-149-5p modulation on MASLD development was assessed in vivo and in vitro using multi-lineage 3D human liver organoids (HLOs) and in Huh7 cells. ResultsMiR-149-5p expression was strongly upregulated in mouse liver from different models of MASLD (2-4 fold increase in ob/ob, db/db mice, high-fat and FPC fed mice). In vivo downregulation of miR-149-5p led to an amelioration of diet-induced hepatic steatosis, inflammation/fibrosis, and to increased whole-body fatty acid consumption. In HLOs, miR-149-5p overexpression promoted lipid accumulation, inflammation and fibrosis. In vitro analyses of human Huh7 cells overexpressing miR-149-5p indicated that glycolysis and intracellular lipid accumulation was promoted, while mitochondrial respiration was impaired. Translatomic analyses highlighted deregulation of multiple miR-149-5p potential targets in hepatocytes involved in MASLD development. ConclusionsMiR-149-5p upregulation contributes to MASLD development by affecting multiple metabolic/inflammatory/fibrotic pathways in hepatocytes. Our results further demonstrate that human liver organoids are a relevant 3D in vitro model to investigate hepatic steatosis and inflammation/fibrosis development. Impact and implicationsThis study delves into the escalating global concern of metabolic dysfunction-associated steatotic liver disease (MASLD). Our research shows compelling evidence that miR-149-5p plays a pivotal role in the disease's development and progression. By employing in vivo and innovative in vitro models using multi-lineage human liver organoids (HLOs), we demonstrate that miR-149-5p upregulation significantly impacts hepatocyte energy metabolism, exacerbating hepatic steatosis and inflammation/fibrosis by modulating a wide network of target genes. These findings not only shed light on the intricate miR-149-5p-dependent molecular mechanisms underlying MASLD, but also underscore the importance of HLOs as valuable 3D in vitro models for studying the disease's pathogenesis.

Loss of NAT10 alleviates maternal high-fat diet-induced hepatic steatosis in male offspring of mice.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming an escalating health problem in pediatric populations. This study aimed to investigate the role of N-acetyltransferase 10 (NAT10) in maternal high-fat diet (HFD)-induced MASLD in offspring at early life. We generated male hepatocyte-specific NAT10 knockout (Nat10HKO) mice and mated them with female Nat10fl/fl mice under chow or HFD feeding. Body weight, liver histopathology, and expression of lipid metabolism-associated genes (Srebp1c, Fasn, Pparα, Cd36, Fatp2, Mttp, and Apob) were assessed in male offspring at weaning. Lipid uptake assays were performed both in vivo and in vitro. The mRNA stability assessment and RNA immunoprecipitation were performed to determine NAT10-regulated target genes. NAT10 deletion in hepatocytes of male offspring alleviated perinatal lipid accumulation induced by maternal HFD, decreasing expression levels of Srebp1c, Fasn, Cd36, Fatp2, Mttp, and Apob while enhancing Pparα expression. Furthermore, Nat10HKO male mice exhibited reduced lipid uptake. In vitro, NAT10 promoted lipid uptake by enhancing the mRNA stability of CD36 and FATP2. RNA immunoprecipitation assays exhibited direct interactions between NAT10 and CD36/FATP2 mRNA. NAT10 deletion in offspring hepatocytes ameliorates maternal HFD-induced hepatic steatosis through decreasing mRNA stability of CD36 and FATP2, highlighting NAT10 as a potential therapeutic target for pediatric MASLD.

A Novel TGFβ Receptor Inhibitor, IPW-5371, Prevents Diet-induced Hepatic Steatosis and Insulin Resistance in Irradiated Mice.

As the number of cancer survivors increases and the risk of accidental radiation exposure rises, there is a pressing need to characterize the delayed effects of radiation exposure and develop medical countermeasures. Radiation has been shown to damage adipose progenitor cells and increase liver fibrosis, such that it predisposes patients to developing metabolic-associated fatty liver disease (MAFLD) and insulin resistance. The risk of developing these conditions is compounded by the global rise of diets rich in carbohydrates and fats. Radiation persistently increases the signaling cascade of transforming growth factor β (TGFβ), leading to heightened fibrosis as characteristic of the delayed effects of radiation exposure. We investigate here a potential radiation medical countermeasure, IPW-5371, a small molecule inhibitor of TGFβRI kinase (ALK5). We found that mice exposed to sub-lethal whole-body irradiation and chronic Western diet consumption but treated with IPW-5371 had a similar body weight, food consumption, and fat mass compared to control mice exposed to radiation. The IPW-5371 treated mice maintained lower fibrosis and fat accumulation in the liver, were more responsive to insulin and had lower circulating triglycerides and better muscle endurance. Future studies are needed to verify the improvement by IPW-5371 on the structure and function of other metabolically active tissues such as adipose and skeletal muscle, but these data demonstrate that IPW-5371 protects liver and whole-body health in rodents exposed to radiation and a Western diet, and there may be promise in using IPW-5371 to prevent the development of MAFLD.

Abstract 2044: Disruption Of DENND5B Attenuates Triglyceride-rich Lipoprotein Secretion From Human Enterocytes And Hepatocytes

Background and Hypothesis: Elevated plasma triacylglycerides (TAGs) are an established risk factor for atherosclerotic cardiovascular disease, and are regulated by dietary absorption via the small intestine and endogenous production by the liver. Our laboratory formerly reported that Dennd5b -deficient mice are protected from diet-induced hepatic steatosis, hyperlipidemia, and atherosclerosis. Electron microscopy imaging of the intestinal epithelium of Dennd5b -/- mice reveals significant lipid accumulation in intracellular chylomicron secretory vesicles, suggesting a post-Golgi chylomicron secretion defect. Given that Dennd5b is expressed by the two major triglyceride-rich lipoprotein (TRL)-secreting organs (liver and small intestine), we hypothesized that disruption of DENND5B attenuates TRL secretion in both of these cell types in humans. Methods and Results: To determine if DENND5B disruption impairs TRL secretion in human cells, we generated DENND5B -/- intestinal epithelial (Caco-2) and hepatocyte (HepG2) cell lines using CRISPR gene editing. Western blots verified DENND5B protein reduction in DENND5B -/- cells. The impact of DENND5B deficiency on TRL secretion was quantified by measuring the cellular and secreted TAG content of DENND5B +/+ and DENND5B -/- cells under standard growth conditions and after oleic acid loading. Caco-2 cells were differentiated on membrane supports for 21 days prior to experiments. DENND5B -/- Caco-2 cells secreted significantly less TAGs compared to wild-type Caco-2 cells (-67.8%, p<0.0001). DENND5B -/- HepG2 cells also had significantly reduced TAG secretion (-91.0%, p<0.0001). Disruption of DENND5B in both cell lines reduced TAG secretion without affecting cellular TAG content. Immunofluorescence microscopy showed intracellular DENND5B protein localization consistent with secretory pathway involvement with detection on a perinuclear structure (likely Golgi), cytosolic vesicles, and plasma membrane. Conclusions: These studies suggest that DENND5B plays a role in TRL secretion from human enterocytes and hepatocytes and provide new model systems for investigating the molecular function of DENND5B in TRL secretion from human cells.

Assessing the Ability to Reverse High Fat High Sugar Diet-Induced Hepatic Steatosis by Dietary Modification

Background: Metabolic syndrome includes a plethora of symptoms ultimately leading to obesity and type 2 diabetes. Increased consumption of ‘Western diets’ rich in fat and sugar increase the development of metabolic syndrome, diabetic obesity and furthermore increase the risk of non-alcoholic fatty liver disease. We aimed to better understand the influence of chronic consumption of a ‘western-type’ high fat-high sugar diet (HFS) on hepatic health and moreover we assessed the ability of dietary modifications (i.e., removal of fat and sugar from the diet) to reverse these detrimental hepatic effects. This would represent what is seen clinically, advocated by a provider in a clinical setting as a first line treatment for diabetic obese patients. Methods: Thirty male C57BL/6J mice were randomly assigned into the following groups: 12-weeks HFS then 12-weeks of standard diet and water (Std), control groups were fed standard chow and water for the entire 24-weeks (lean control) or fed HFS diet for the entire 24-weeks (HFS). At the end of the 24-week diet study, livers were removed and fixed (for sectioning and staining with Oil-Red-O or trichrome and quantified with Image J) or frozen and kept at -80°C (for PCR studies and assays). Serum was collected for assays. Results: At the end of the diet study, body weight was significantly increased 1.5-fold by HFS and reduced 34% (p<0.05) in the Std group. Liver weight/body weight ratio followed the same trend as body weight. Percent fat area, total number of lipid droplets and average total lipid area were all significantly increased in the HFS group versus lean controls and were all significantly reduced by Std (p<0.05). Serum ALT activity was increased 3-fold by HFS and then reduced to lean levels by Std. Serum TNF-α and MCP1 levels followed the same trend. Serum TBARS were significantly increased 1.6-fold, but unchanged with Std. Trichrome analysis demonstrated deposition of collagen in liver from HFS fed mice (15.53% area), which was significantly reversed by the switch to Std (4.58% area). This data will be complemented with mRNA levels currently being run for collagens 1, 3, 4. Preliminary findings indicate that HFS fed mice have a significant increase in expression of collagen-1 but not collagen-3. We aim to further explore the metabolic mechanisms involved in the reversal of hepatic steatosis and fibrosis between the three diet groups. Conclusions: We conclude that removal of the HFS diet and switching to standard chow and water (Std) is an effective treatment regimen and results in robust reversal of hepatic steatosis along with reversal of collagen deposition, with concomitant beneficial changes in key serum markers of hepatic health, systemic inflammatory profile, and body/liver weight. The mechanistic pathways triggering these effects are being explored. Midwestern-Arizona Alzheimer’s consortium and Midwestern University Intramural Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Surfactant protein A promotes western diet-induced hepatic steatosis and fibrosis in mice

Metabolic dysfunction-associated steatotic liver disease (MASLD) remains the most common cause of liver disease in the United States due to the increased incidence of metabolic dysfunction and obesity. Surfactant protein A (SPA) regulates macrophage function, strongly binds to lipids, and is implicated in renal and idiopathic pulmonary fibrosis (IPF). However, the role of SPA in lipid accumulation, inflammation, and hepatic fibrosis that characterize MASLD remains unknown. SPA deficient (SPA−/−) and age-matched wild-type (WT) control mice were fed a Western diet for 8 weeks to induce MASLD. Blood and liver samples were collected and used to analyze pathological features associated with MASLD. SPA expression was significantly upregulated in livers of mice with MASLD. SPA deficiency attenuated lipid accumulation along with downregulation of genes involved in fatty acid uptake and reduction of hepatic inflammation as evidenced by the diminished macrophage activation, decreased monocyte infiltration, and reduced production of inflammatory cytokines. Moreover, SPA−/− inhibited stellate cell activation, collagen deposit, and liver fibrosis. These results highlight the novel role of SPA in promoting fatty acid uptake into hepatocytes, causing excessive lipid accumulation, inflammation, and fibrosis implicated in the pathogenesis of MASLD.

Inhibition of ACOX1 enhances the therapeutic efficacy of obeticholic acid in treating non-alcoholic fatty liver disease and mitigates its lipotoxicity.

High-dose Obeticholic acid exhibits promise for non-alcoholic fatty liver disease (NAFLD) treatment but can induce lipotoxicity. Our study sought to understand this mechanism and propose a solution. In a non-alcoholic fatty liver disease (NAFLD) model induced by a high-fat diet in FXR-/- mice, we pinpointed that FXR regulated the expression of ACOX1 through RNA-Seq analysis. In the livers of FXR-/- mice, both ACOX1 mRNA and protein expression notably decreased. In both HL-7702 and HEP-G2 cells, the silencing of FXR through shRNA plasmids decreased ACOX1 expression, while FXR activation with GW4064 increased it. These effects were reversible with the ACOX1-specific inhibitor, 10,12-Tricosadiynoic acid. In the NAFLD model of FXR-/- mice, The activation of ACOX1 is correlated with elevated serum LDL, triglycerides, and aggravated hepatic steatosis. However, the combination of 10,12-Tricosadiynoic acid with low-dose obeticholic acid effectively treated hepatic steatosis, reducing LDL levels in the NAFLD model of wild-type mice. This combination therapy demonstrated efficacy comparable to high-dose obeticholic acid alone. Notably, the combined drug regimen treats hepatic steatosis by inhibiting the IL-1β and α-SMA pathways in NAFLD. Combining ACOX1-specific inhibitors with low-dose obeticholic acid effectively treats high-fat diet-induced hepatic steatosis and reduces serum LDL. This approach enhances the therapeutic effects of obeticholic acid and mitigates its lipotoxicity by inhibiting the IL-1β and α-SMA pathways.

Lian-Mei-Yin formula alleviates diet-induced hepatic steatosis by suppressing Yap1/FOXM1 pathway-dependent lipid synthesis.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with a global prevalence of 25%. Patients with NAFLD are more likely to suffer from advanced liver disease, cardiovascular disease, or type II diabetes. However, unfortunately, there is still a shortage of FDA-approved therapeutic agents for NAFLD. Lian-Mei-Yin (LMY) is a traditional Chinese medicine formula used for decades to treat liver disorders. It has recently been applied to type II diabetes which is closely related to insulin resistance. Given that NAFLD is another disease involved in insulin resistance, we hypothesize that LMY might be a promising formula for NAFLD therapy. Herein, we verify that the LMY formula effectively reduces hepatic steatosis in diet-induced zebrafish and NAFLD model mice in a time- and dose-dependent manner. Mechanistically, LMY suppresses Yap1-mediated Foxm1 activation, which is crucial for the occurrence and development of NAFLD. Consequently, lipogenesis is ameliorated by LMY administration. In summary, the LMY formula alleviates diet-induced NAFLD in zebrafish and mice by inhibiting Yap1/Foxm1 signaling-mediated NAFLD pathology.

Graphislactone A, a Fungal Antioxidant Metabolite, Reduces Lipogenesis and Protects against Diet-Induced Hepatic Steatosis in Mice.

Graphislactone A (GPA), a secondary metabolite derived from a mycobiont found in the lichens of the genus Graphis, exhibits antioxidant properties. However, the potential biological functions and therapeutic applications of GPA at the cellular and animal levels have not yet been investigated. In the present study, we explored the therapeutic potential of GPA in mitigating non-alcoholic fatty liver disease (NAFLD) and its underlying mechanisms through a series of experiments using various cell lines and animal models. GPA demonstrated antioxidant capacity on a par with that of vitamin C in cultured hepatocytes and reduced the inflammatory response induced by lipopolysaccharide in primary macrophages. However, in animal studies using an NAFLD mouse model, GPA had a milder impact on liver inflammation while markedly attenuating hepatic steatosis. This effect was confirmed in an animal model of early fatty liver disease without inflammation. Mechanistically, GPA inhibited lipogenesis rather than fat oxidation in cultured hepatocytes. Similarly, RNA sequencing data revealed intriguing associations between GPA and the adipogenic pathways during adipocyte differentiation. GPA effectively reduced lipid accumulation and suppressed lipogenic gene expression in AML12 hepatocytes and 3T3-L1 adipocytes. In summary, our study demonstrates the potential application of GPA to protect against hepatic steatosis in vivo and suggests a novel role for GPA as an underlying mechanism in lipogenesis, paving the way for future exploration of its therapeutic potential.

Repurposing lansoprazole to alleviate metabolic syndrome via PHOSPHO1 inhibition

Drug repurposing offers an efficient approach to therapeutic development. In this study, our bioinformatic analysis first predicted an association between obesity and lansoprazole (LPZ), a commonly prescribed drug for gastrointestinal ulcers. We went on to show that LPZ treatment increased energy expenditure and alleviated the high-fat diet-induced obesity, insulin resistance, and hepatic steatosis in mice. Treatment with LPZ elicited thermogenic gene expression and mitochondrial respiration in primary adipocytes, and induced cold tolerance in cold-exposed mice, suggesting the activity of LPZ in promoting adipose thermogenesis and energy metabolism. Mechanistically, LPZ is an efficient inhibitor of adipose phosphocholine phosphatase 1 (PHOSPHO1) and produces metabolic benefits in a PHOSPHO1-dependent manner. Our results suggested that LPZ may stimulate adipose thermogenesis by inhibiting the conversion of 2-arachidonoylglycerol-lysophosphatidic acid (2-AG-LPA) to 2-arachidonoylglycerol (2-AG) and reduce the activity of the thermogenic-suppressive cannabinoid receptor signaling. In summary, we have uncovered a novel therapeutic indication and mechanism of LPZ in managing obesity and its related metabolic syndrome, and identified a potential metabolic basis by which LPZ improves energy metabolism.

Lacticaseibacillus rhamnosus HF01 fermented yogurt alleviated high-fat diet-induced obesity and hepatic steatosis via the gut microbiota-butyric acid-hepatic lipid metabolism axis.

The objective of this study was to investigate the anti-obesity effects and underlying mechanism of Lacticaseibacillus rhamnosus HF01 fermented yogurt (HF01-Y). Herein, obesity was induced in mice through a high-fat diet and the changes in the gut microbiota were evaluated using 16S rRNA gene sequencing, combined with the expression levels of the liver AMPK signaling pathway to analyze the potential relationship between HF01-Y-mediated gut microbiota and obesity. The results showed that supplementation with HF01-Y improved obesity-related phenotypes in mice, including reduced body weight, improved serum lipid profiles, and decreased hepatic lipid droplet formation. In addition, HF01-Y altered the composition of the gut microbiota in obese mice, significantly upregulated norank_f__Muribaculaceae, unclassified_c__Clostridia, Blautia, unclassified_o__Bacteroidales, and Rikenellaceae_RC9_gut_group, while downregulating unclassified_f__Desulfovibrionaceae, Colidextribacter, and unclassified_f__Oscillospiraceae. These alterations led to an increase of the cecum butyric acid content, which in turn indirectly promoted the activation of the AMPK signaling pathway, subsequently, inhibited fat synthesis, and promoted fatty acid oxidation related gene expression. Therefore, HF01-Y was likely to alleviate hepatic fat and relieve obesity by modulating the gut microbiota-butyric acid-hepatic lipid metabolism axis, ultimately promoting host health.

Mitigation of high-fat diet-induced hepatic steatosis by thyme (Thymus quinquecostatus Celak) polyphenol-rich extract (TPE): insights into gut microbiota modulation and bile acid metabolism.

Our previous study demonstrated that thyme polyphenol-rich extract (TPE) mitigated hepatic injury induced by a high-fat diet (HFD) through the regulation of lipid metabolism, promotion of short-chain fatty acid production, enhancement of intestinal barrier function, and attenuation of inflammation. In this study, we aimed to further elucidate additional mechanisms underlying TPE-mediated preventive effects on hepatic steatosis, with a specific focus on its impact on the gut microbiota and bile acid (BA) metabolism in HFD-fed mice. TPE treatment resulted in a significant reduction in serum total BA levels and a notable increase in fecal total BA levels. In particular, elevations in fecal conjugated BA levels, in turn, impede intestinal farnesoid X receptor (FXR) signaling, thereby enhancing hepatic synthesis and fecal excretion of BAs. The downregulated mRNA expression levels of intestinal Fxr and Fgf15, and hepatic Fgfr4, along with the upregulated mRNA expression levels of Cyp7a1 and Cyp27a1 after TPE treatment also prove the above inference. Meanwhile, TPE appeared to promote BA efflux and enterohepatic circulation, as evidenced by changes in the mRNA levels of Bsep, Ntpc, Shp, Asbt, Ibabp, and Ostα/β. TPE also modulated the gut microbiota and was characterized by an increased relative abundance of Lactobacillus. Furthermore, antibiotic treatment depleted the intestinal flora in mice, also abrogating the hepatoprotective effect of TPE against NAFLD. These findings collectively indicate that TPE effectively mitigates HFD-induced NAFLD by modulating the gut-liver axis, specifically targeting the gut microbiota and bile acid metabolism.

Preventive effects of caffeine on nicotine plus high-fat diet-induced hepatic steatosis and gain weight: a possible explanation for why obese smokers with high coffee consumption tend to be leaner.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent liver disorder, affecting approximately 25 % of the population. Coffee-drinking obese smokers exhibit lower body weights and decreased NAFLD rates, but the reasons behind this remain unclear. Additionally, the effect of nicotine, the main component of tobacco, on the development of NAFLD is still controversial. Our study aimed to explore the possible reasons that drinking coffee could alleviate NAFLD and gain weight and identify the real role of nicotine in NAFLD of obese smokers. A NAFLD model in mice was induced by administering nicotine and a high-fat diet (HFD). We recorded changes in body weight and daily food intake, measured the weights of the liver and visceral fat, and observed liver and adipose tissue histopathology. Lipid levels, liver function, liver malondialdehyde (MDA), superoxide dismutase (SOD), serum inflammatory cytokine levels and the expression of hepatic genes involved in lipid metabolism were determined. Our results demonstrated that nicotine exacerbated the development of NAFLD and caffeine had a hepatoprotective effect on NAFLD. The administration of caffeine could ameliorate nicotine-plus-HFD-induced NAFLD by reducing lipid accumulation, regulating hepatic lipid metabolism, alleviating oxidative stress, attenuating inflammatory response and restoring hepatic functions. Theseresultsmight explainwhyobese smokers with high coffee consumption exhibit the lower incidencerate of NAFLD and tend to be leaner. It is essential to emphasise that the detrimental impact of smoking on health is multifaceted. Smoking cessation remains the sole practical and effective strategy for averting the tobacco-related complications and reducing the risk of mortality.

Isomalt attenuates hepatic steatosis in rats via modulating gut microbiota and its metabolic function

Growing studies have shown the preventive effects of isomalt against metabolic diseases, nevertheless, its efficacy and action mechanisms on nonalcoholic fatty liver disease (NAFLD) remain unknown. Herein, isomalt supplementation significantly attenuated the high-sucrose diet-induced hepatic steatosis. Mechanically, dietary isomalt restored hepatic de novo lipogenesis dysfunction and intestinal epithelial integrity. Moreover, isomalt consumption regulated gut microbiota composition, including improving abundance of probiotic Akkermansia, but suppressing pathogens Acinetobacter and Corynebacterium_1. Quantification analyses of short-chain fatty acids showed that isomalt reduced faecal acetate concentrations, whereas elevated propionate and butyrate in hepatic steatosis. Additionally, targeted metabolomics profiling of tryptophan metabolism showed that isomalt increased faecal levels of 5-hydroxytryptophan, indole-3-carboxaldehyde and kynurenic acid, but reduced concentrations of 5-hydroxyindoleacetic acid and xanthurenic acid in rats. Thereby, our data demonstrate that dietary isomalt attenuates hepatic steatosis possibly via modulation of gut microbiota and its metabolic function, which provides new insights into preventing and treating NAFLD in future.