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Betaine is the major water-soluble component of Lycium chinensis. Although there are reports of a protective effect of betaine on fatty liver disease, the underlying mechanisms are unclear. We attempted to elucidate the molecular regulation of betaine on hyperglycemia-induced hepatic lipid accumulation via Forkhead box O (FoxO)6 activation. HepG2 cells and liver tissue isolated from db/db mice treated with betaine were used. The present study investigated whether betaine ameliorates hepatic steatosis by inhibiting FoxO6/peroxisome proliferator-activated receptor gamma (PPARγ) signaling in liver cells. Interestingly, betaine notably decreased lipid accumulation in tissues with FoxO6-induced mRNA expression of lipogenesis-related genes. Furthermore, betaine inhibited the FoxO6 interaction with PPARγ and cellular triglycerides in high-glucose- or FoxO6-overexpression-treated liver cells. In addition, we confirmed that betaine administration via oral gavage significantly ameliorated hepatic steatosis in db/db mice. We conclude that betaine ameliorates hepatic steatosis, at least in part, by inhibiting the interaction between FoxO6 and PPARγ, thereby suppressing lipogenic gene transcription.

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OBJECTIVE: Ginsenoside Re, a unique tetracyclic triterpenoid compound found in ginseng, has been suggested in previous reports to improve non-alcoholic fatty liver disease (NAFLD) by modulating lipid imbalance. This study aims to elucidate the potential mechanisms of Ginsenoside Re in treating NAFLD through a combination of bioinformatics analysis and biological experiments. METHODS: Network pharmacology methods were employed to systematically depict the effective components and mechanisms of Ginsenoside Re in improving NAFLD. Molecular docking was utilized to evaluate the binding affinity of Ginsenoside Re with NAFLD-related targets and identify potential targets. NAFLD-related target genes were obtained from the GEO database for gene enrichment analysis, revealing signaling pathways, biological processes, and gene differential expression. Finally, animal experiments were conducted to verify the mechanism of action of Ginsenoside Re in NAFLD. RESULTS: Network pharmacology analysis revealed that Ginsenoside Re improves NAFLD by modulating targets such as AKT1 and TLR4, findings corroborated by molecular docking, GEO database analysis, and experimental validation. Further investigation found that Ginsenoside Re ameliorates lipid metabolism disorders and inflammatory responses induced by NAFLD by modulating the PI3K/AKT and TLR4/NF-κB signaling pathways. CONCLUSION: Our study demonstrates the pharmacological effects of Ginsenoside Re in treating NAFLD, implicating multiple components, targets, and pathways. This provides a solid foundation for considering Ginsenoside Re as an alternative therapy for NAFLD, with promising clinical applications.

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Nanoplastics (NPs) continue to accumulate in global aquatic and terrestrial systems, posing a potential threat to human health through the food chain and/or other pathways. Both in vivo and in vitro studies have confirmed that the liver is one of the main organs targeted for the accumulation of NPs in living organisms. However, whether exposure to NPs induces size-dependent disorders of liver lipid metabolism remains controversial, and the reversibility of NPs-induced hepatotoxicity is largely unknown. In this study, the effects of long-term exposure to environmentally relevant doses of polystyrene nanoplastics (PS-NPs) on lipid accumulation were investigated in terms of autophagy and lysosomal mechanisms. The findings indicated that hepatic lipid accumulation was more pronounced in mice exposed to 100 nm PS-NPs compared to 500 nm PS-NPs. This effect was effectively alleviated after 50 days of self-recovery for 100 nm and 500 nm PS-NPs exposure. Mechanistically, although PS-NPs exposure activated autophagosome formation through ERK (mitogen-activated protein kinase 1)/mTOR (mechanistic target of rapamycin kinase) signaling pathway, the inhibition of Rab7 (RAB7, member RAS oncogene family), CTSB (cathepsin B), and CTSD (cathepsin D) expression impaired lysosomal function, thereby blocking autophagic flux and contributing to hepatic lipid accumulation. After termination of PS-NPs exposure, lysosomal exocytosis was responsible for the clearance of PS-NPs accumulated in lysosomes. Furthermore, impaired lysosomal function and autophagic flux inhibition were effectively alleviated. This might be the main reason for the alleviation of PS-NPs-induced lipid accumulation after recovery. Collectively, we demonstrate for the first time that lysosomes play a dual role in the persistence and reversibility of hepatotoxicity induced by environmental relevant doses of NPs, which provide novel evidence for the prevention and intervention of liver injury associated with nanoplastics exposure.

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OBJECTIVE: The aim of this study was to explore the effect of the ketogenic diet (KD) on ß-cell dedifferentiation and hepatic lipid accumulation in db/db mice. METHODS: After a 3-wk habituation, male db/db mice ages 8 wk were assigned into one of three groups: normal diet (ND), KD, and 75% calorie restriction (CR) group. Free access to a standard diet, a KD, and 75% of a standard diet, respectively, were given to each group. Additionally, sex-matched 8-wk-old C57BL/6 mice were used to construct a control (C) group. After a 4-wk dietary intervention, mouse body weight, fasting blood glucose (FBG), blood lipids, fasting insulin (FINS), glucose tolerance, and ß-hydroxybutyric acid level were measured. The morphologies of the islet and liver were observed by hematoxylin and eosin staining. Positive expressions of ß-cell-specific transcription factors in mouse islets were determined by double immunofluorescence staining. The size and number of lipid droplets in mouse liver were examined by Oil Red O staining. Real-time quantitative reverse transcription polymerase chain reaction detected relative levels of adipogenesis-associated and lipolysis-associated genes in mouse liver. Additionally, expressions of CD36 protein in the mouse liver were determined by immunohistochemical staining and Western blot. RESULTS: After a 4-wk dietary intervention, FBG, FINS, and glucose area under the curve in the KD group became significantly lower than in the ND group (all P < 0.05). Regular morphology of mouse islets was observed in the KD group, with an increased number of islet cells. The KD significantly reversed the decrease in ß-cell number, disarrangement of ß-cells, decline of ß/α-cell ratio, and downregulation of ß-cell-specific transcription factors in db/db mice. Serum levels of triacylglycerol, total cholesterol, and low-density lipoprotein cholesterol were comparable between the ND and KD groups. In contrast, serum triacylglycerol levels were significantly lower in the CR group than in the ND group (P < 0.05). Vacuolar degeneration and lipid accumulation in the liver were more prominent in the KD group than in the ND and CR groups. The mRNA levels of Pparα and Acox1 in the KD group were lower than those in the ND group, although no significant differences were detected. Relative levels of Cd36 and inflammatory genes in the mouse liver were significantly higher in the KD group than in the ND group (all P < 0.05). CONCLUSION: The KD significantly reduced FBG and FINS and improved glucose tolerance in db/db mice by upregulating ß-cell-specific transcription factors and reversing ß-cell dedifferentiation. However, the KD also induced hepatic lipid accumulation and aggravated inflammatory response in the liver of db/db mice.

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Perfluorodecanoic acid (PFDA), an enduring and harmful organic pollutant, is widely employed in diverse food-related sectors. Our previous studies have provided evidence that PFDA has the potential to facilitate obesity and hepatic fat accumulation induced by high-fat diet (HFD) intake. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, has been suggested to possess potential preventive effects against metabolic abnormalities and fatty liver. The purpose of this research was to investigate the effects of EGCG on PFDA-exacerbated adiposity and hepatic lipid accumulation in HFD-fed mice. The results showed that EGCG reduced body weight gain; tissue and organ weights; blood glucose, serum insulin, HOMA-IR, leptin, and lipid parameters; serum inflammatory cytokines (IL-1ß, IL-18, IL-6, and TNF-α); and hepatic lipid accumulation in PFDA-exposed mice fed an HFD. Further work showed that EGCG improved liver function and glucose homeostasis in mice fed an HFD and co-exposed to PFDA. The elevated hepatic mRNA levels of SREBP-1 and associated lipogenic genes, NLRP3, and caspase-1 in PFDA-exposed mice fed an HFD were significantly decreased by EGCG. Our work provides evidence for the potential anti-obesity effect of EGCG on co-exposure to HFD and PFDA and may call for further research on the bioactivity of EGCG to attenuate the endocrine disruption effects of long-term exposure to pollutants.

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The liver is an essential multifunctional organ, which constantly communicates with nearly all tissues. It has raised the concern that microgravity exposure can lead to liver dysfunction and metabolic syndromes. However, molecular mechanisms and intervention measures of the adverse effects of microgravity on hepatocytes are limited. In this study, we utilized the random positioning machine culture system to investigate the adverse effects on hepatocytes under simulated microgravity (SMG). Our results showed that SMG impaired hepatocyte viability, causing cell cycle arrest and apoptosis. Compared to normal gravity, it also triggered lipid accumulation, elevated triglyceride (TG) and ROS levels, and impaired mitochondria function in hepatocytes. Furthermore, RNA sequencing results showed that SMG upregulated genes implicated in lipid metabolisms, including PPARγ, PLIN2, CD36, FABPs, etc. Importantly, all these defects can be suppressed by melatonin, a potent antioxidant secreted by the pineal gland, suggesting its potential use of therapeutic intervention.

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Epidemiological studies found that the intake of dairy products is associated with an increased amount of circulating odd-chain fatty acids (OCFA, C15:0 and C17:0) in humans and further indicate that especially C17:0 is associated with a lower incidence of type 2 diabetes. However, causal relationships are not elucidated. To provide a mechanistic link, mice were fed high-fat (HF) diets supplemented with either milk fat or C17:0 for 20 weeks. Cultured primary mouse hepatocytes were used to distinguish differential effects mediated by C15:0 or C17:0. Despite an induction of OCFA after both dietary interventions, neither long-term milk fat intake nor C17:0 supplementation improved diet-induced hepatic lipid accumulation and insulin resistance in mice. HF feeding with milk fat actually deteriorates liver inflammation. Treatment of primary hepatocytes with C15:0 and C17:0 suppressed JAK2/STAT3 signaling, but only C15:0 enhanced insulin-stimulated phosphorylation of AKT. Overall, the data indicate that the intake of milk fat and C17:0 do not mediate health benefits, whereas C15:0 might be promising in further studies.

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Advanced lipoxidation end products (ALEs) are formed by modifying proteins with lipid oxidation products. The health effects of ALEs formed in vivo have been extensively studied. However, the digestibility, safety, and health risk of ALEs in heat-processed foods remain unclear. This investigation was performed to determine the structure, digestibility, and effect on the mice liver of dietary ALEs. The results showed that malondialdehyde (MDA) was able to alter the structure of myofibrillar proteins (MPs) to form linear, loop, and cross-linked types of Schiff bases and dihydropyridine derivatives under simulated heat processing, leading to the intra- and intermolecular aggregation of MPs and, thus, reducing the digestibility of MPs. In addition, dietary ALE intake resulted in abnormal liver function and lipid accumulation in mice. The core reason for these adverse effects was the destructive effect of ALEs on the intestinal barrier. Because the damage to the intestinal barrier leads to an increase in lipopolysaccharide levels in the liver, it induces liver damage by modulating hepatic lipid metabolism.

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Cypermethrin (CP), widely used as a broad-spectrum pesticide, has raised concerns over its frequent presence in the environment and potential health risks. The present study focused on incorporating the gut-organ axis theory to reinterpret the toxicological effects and mechanisms following CP exposure at environmentally relevant concentrations (0.1 mg/kg/d and 0.5 mg/kg/d) in pubertal male rats. The results showed alterations in histopathological and organosomatic indices in the liver, brain, and epididymis. Through multiomics network analysis, it was found that Lachnospiraceae and Ruminococcaceae may contribute to the alteration in serum L-carnitine and trigonelline, leading to hepatic lipid accumulation following CP exposure. Additionally, Ruminococcaceae, Lachnospiraceae, and Porphyromonadaceae were associated with CP-induced glutamatergic hypofunction and overproduction of TNF-α, potentially contributing to the brain neurotoxicity. Overall, the study provides important insights into the potential mechanisms underlying CP-induced toxicity and highlights the need for continued research to fully understand the implications for CP-induced health risks. The incorporation of the gut-organ axis theory in the study provides a promising avenue for future research into the potential interactions between gut microbiota and organ toxicity, and the potential for targeted interventions to mitigate the adverse effects of environmental toxins.

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Background: Garcinia cambogia is widely used as a weight-loss supplement, and it is reported to be negatively associated with metabolic diseases including insulin resistance (IR), type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and dyslipidemia. Objective: This study aimed to investigate the effect of G. cambogia water extract (GE) on high-fat diet (HFD)-induced obesity, IR, and hepatic lipid accumulation. Design: C57BL/6 male mice were fed HFD with or without GE, GED and GEP for 16 weeks, and the mice were subjected to insulin tolerance tests and liver histological analysis. The hydroxycitric acid (HCA) levels of GE, GED, and GEP were measured by high-performance liquid chromatography. Results: The results showed that GE significantly reduced HFD-induced body weight gain (P < 0.001), alleviated IR (P < 0.01), reduced serum total cholesterol (TC) (P < 0.001), and attenuated HFD-induced hepatic lipid accumulation. To investigate the constituent that was responsible for these effects, we separated GE into the component that dissolved in ethanol (GED) and the component that was precipitated by ethanol (GEP). Further mouse experiments showed that both GED and GEP were effective, but GED (which was used at a dose of 4 g/L) was more effective than GEP (which was used at a lower dose of 1 g/L). The HCA levels in GED and GEP were similar, although less than in GE. HCA may be the effective component in GE. Conclusion: This study provides evidence that G. cambogia can be used as a natural supplement to alleviate IR and hepatic lipid accumulation.

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CONTEXT: Non-alcoholic fatty liver disease (NAFLD) is a common liver disease, accompanied by liver lipid accumulation and inflammation. JianPi-QingHua formula (JPQH), a Chinese herbal formula, exhibits effects on obesity and T2DM. However, the hepatoprotective effect of JPQH has not been elucidated. OBJECTIVE: To investigate the hepatoprotective effect of JPQH in NAFLD induced by a high-fat diet (HFD) in mice. MATERIALS AND METHODS: C57BL/6J mice were divided into four groups and fed a normal-fat diet (ND), high-fat diet (HFD), HFD + JPQH (2.5 g/kg), or HFD + metformin (300 mg/kg) for 6 weeks, respectively. Furthermore, the body weight, epididymal fat mass, blood glucose, and liver weight were measured. Serum total cholesterol (TC), triglycerides (TG), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were performed. Hematoxylin and eosin staining and Oil Red O staining were observed in hepatic histopathological changes. Western blotting and quantitative real-time polymerase chain reaction were utilized to assess the key protein expression of hepatic lipid metabolism and inflammation. RESULTS: Compared with the HFD group, JPQH could reduce body weight, epididymal fat mass, blood glucose and liver weight (p < 0.05), and markedly decreased the levels of serum TC, TG, ALT, AST (p < 0.05). Additionally, JPQH improved liver pathological changes. Consistent with the hepatic histological analysis, JPQH intervention suppressed lipid accumulation and inflammatory responses. Mechanistically, JPQH boosted SIRT1/AMPK signalling, and attenuated NF-κB pathway, which suppressed inflammatory responses. DISCUSSION AND CONCLUSIONS: These findings indicate that JPQH supplementation protected against HFD-induced NAFLD by regulating SIRT1/AMPK/NF-κB pathway, which provides a theoretical basis for the clinical treatment of patients with NAFLD.

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Microalgae are attracting attention as a next-generation alternative source of protein and essential fatty acids that do not consume large amounts of water or land. Chaetoceros gracilis (C. gracilis)-a marine microalga-is rich in proteins, fucoxanthin, and eicosapentaenoic acid (EPA). Growing evidence indicates that dietary fucoxanthin and EPA have beneficial effects in humans. However, none of these studies have shown that dietary C. gracilis has beneficial effects in mammals. In this study, we investigated the effects of dietary C. gracilis on lipid abnormalities in Sprague-Dawley rats fed a high-sucrose cholesterol-containing diet. Dried C. gracilis was added to the control diet at a final dose of 2 or 5% (w/w). After four weeks, the soleus muscle weights were found to be dose-responsive to C. gracilis and showed a tendency to increase. The hepatic triglyceride and total cholesterol levels were significantly reduced by C. gracilis feeding compared to those in the control group. The activities of FAS and G6PDH, which are related to fatty acid de novo synthesis, were found to be dose-responsive to C. gracilis and tended to decrease. The hepatic glycerol content was also significantly decreased by C. gracilis feeding, and the serum HDL cholesterol levels were significantly increased, whereas the serum levels of cholesterol absorption markers (i.e., campesterol and ß-sitosterol) and the hepatic mRNA levels of Scarb1 were significantly decreased. Water-soluble metabolite analysis showed that the muscular contents of several amino acids, including leucine, were significantly increased by C. gracilis feeding. The tendency toward an increase in the weight of the soleus muscle as a result of C. gracilis feeding may be due to the enhancement of muscle protein synthesis centered on leucine. Collectively, these results show that the oral administration of C. gracilis alleviates hepatic lipid accumulation in rats fed a high-sucrose and cholesterol-containing diet, indicating the potential use of C. gracilis as a food resource.

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Alcoholic liver disease(ALD), with its increasing morbidity and mortality, has seriously and extensively affected the health of people worldwide. Methyl ferulic acid(MFA) has been proven to significantly inhibit alcohol-induced lipid production in L02 cells through the AMP-activated protein kinase(AMPK) pathway, but its in-depth mechanism remains unclear. This study aimed to further clarify the mechanism of MFA in improving lipid accumulation in L02 cells through the microRNA-378b(miR-378b)-mediated calcium/calmodulin-dependent protein kinase kinase 2(CaMKK2)-AMPK signaling pathway based on existing researches. L02 cells were induced by 100 mmol·L~(-1) ethanol for 48 h to establish the model of ALD in vitro, and 100, 50, and 25 µmol·L~(-1) concentration of MFA was treated. MiR-378b plasmids(containing the overexpression plasmid-miR-378b mimics, silence plasmid-miR-378b inhibitor, and their respective negative control-miR-378b NCs) were transfected into L02 cells by electroporation to up-regulate or down-regulate the levels of miR-378b in L02 cells. The levels of total cholesterol(TC) and triglyceride(TG) in cells were detected by commercial diagnostic kits and automatic biochemical analyzers. The expression levels of miR-378b in L02 cells were detected by real-time quantitative polymerase chain reaction(qRT-PCR). CaMKK2 mRNA levels were detected by PCR, and protein expressions of related factors involved in lipid synthesis, decomposition, and transport in lipid metabolism were detected by Western blot. The results displayed that ethanol significantly increased TG and TC levels in L02 cells, while MFA decreased TG and TC levels. Ethanol up-regulated the miR-378b level, while MFA effectively inhibited the miR-378b level. The overexpression of miR-378b led to lipid accumulation in ethanol-induced L02 cells, while the silence of miR-378b improved the lipid deposition induced by ethanol. MFA activated the CaMKK2-AMPK signaling pathway by lowering miR-378b, thus improving lipid synthesis, decomposition, and transport, which improved lipid deposition in L02 cells. This study shows that MFA improves lipid deposition in L02 cells by regulating the CaMKK2-AMPK pathway through miR-378b.

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In modern life, the fluctuation of dietary protein levels is common, in particular, for low-income populations. However, its effect on human health is little known. Alternating changes of low and high casein or pork protein were used to simulate the fluctuation of dietary protein content in mice. Hepatic lipid accumulation showed a fast response to alternating changes of low- and high-protein diets. Correspondingly, some gut microbiota and tryptophan metabolite composition also showed a fast response to dietary protein changes. The fast response of 3-hydroxykynurenine (3-HK) was proven to inhibit hepatic lipid accumulation in vitro. Therefore, intermittent protein diets modulated hepatic lipid accumulation through 3-HK. These findings highlighted the sensitivity of hepatic lipid accumulation to dietary protein levels.

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Alcoholic liver disease(ALD), with its increasing morbidity and mortality, has seriously and extensively affected the health of people worldwide. Methyl ferulic acid(MFA) has been proven to significantly inhibit alcohol-induced lipid production in L02 cells through the AMP-activated protein kinase(AMPK) pathway, but its in-depth mechanism remains unclear. This study aimed to further clarify the mechanism of MFA in improving lipid accumulation in L02 cells through the microRNA-378b(miR-378b)-mediated calcium/calmodulin-dependent protein kinase kinase 2(CaMKK2)-AMPK signaling pathway based on existing researches. L02 cells were induced by 100 mmol·L~(-1) ethanol for 48 h to establish the model of ALD in vitro, and 100, 50, and 25 μmol·L~(-1) concentration of MFA was treated. MiR-378b plasmids(containing the overexpression plasmid-miR-378b mimics, silence plasmid-miR-378b inhibitor, and their respective negative control-miR-378b NCs) were transfected into L02 cells by electroporation to up-regulate or down-regulate the levels of miR-378b in L02 cells. The levels of total cholesterol(TC) and triglyceride(TG) in cells were detected by commercial diagnostic kits and automatic biochemical analyzers. The expression levels of miR-378b in L02 cells were detected by real-time quantitative polymerase chain reaction(qRT-PCR). CaMKK2 mRNA levels were detected by PCR, and protein expressions of related factors involved in lipid synthesis, decomposition, and transport in lipid metabolism were detected by Western blot. The results displayed that ethanol significantly increased TG and TC levels in L02 cells, while MFA decreased TG and TC levels. Ethanol up-regulated the miR-378b level, while MFA effectively inhibited the miR-378b level. The overexpression of miR-378b led to lipid accumulation in ethanol-induced L02 cells, while the silence of miR-378b improved the lipid deposition induced by ethanol. MFA activated the CaMKK2-AMPK signaling pathway by lowering miR-378b, thus improving lipid synthesis, decomposition, and transport, which improved lipid deposition in L02 cells. This study shows that MFA improves lipid deposition in L02 cells by regulating the CaMKK2-AMPK pathway through miR-378b.

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A 12-week experiment was conducted to explore the effects of betaine and/or TMAO on growth, hepatic health, gut microbiota, and serum metabolites in Megalobrama amblycephala fed with high-carbohydrate diets. The diets were as follows: CD group (control diet, 28.5% carbohydrate), HCD group (high-carbohydrate diet, 38.2% carbohydrate), HBD group (betaine-added diet, 38.3% carbohydrate + 1.2% betaine), HTD group (TMAO-added diet, 38.2% carbohydrate + 0.2% TMAO), and HBT group (diet added with both betaine and TMAO, 38.2% carbohydrate + 1.2% betaine + 0.2% TMAO). The results showed that the hepatosomatic index (HSI); whole-body crude fat; hepatic lipid accumulation; messenger RNA expression levels of gk, fpbase, g6pase, ahas, and bcat; serum branched-chain amino acids (BCAAs); ratio of Firmicutes-to-Bacteroidetes; and abundance of the genus Aeromonas were all significantly increased, while the abundance levels of the genus Lactobacillus and phyla Tenericutes and Bacteroidetes were drastically decreased in the HCD group. Compared with the HCD group, the HSI; whole-body crude fat; hepatic lipid accumulation; expression levels of fbpase, g6pase, pepck, ahas, and bcat; circulating BCAA; ratio of Firmicutes-to-Bacteroidetes; and abundance levels of the genus Aeromonas and phyla Tenericutes and Bacteroidetes were significantly downregulated in the HBD, HTD, and HBT groups. Meanwhile, the expression levels of pk were drastically upregulated in the HBD, HTD, and HBT groups as well as the abundance of Lactobacillus in the HBT group. These results indicated that the supplementation of betaine and/or TMAO in high-carbohydrate diets could affect the hepatic lipid accumulation and glycometabolism of M. amblycephala by promoting glycolysis, inhibiting gluconeogenesis and biosynthesis of BCAA, and mitigating the negative alteration of gut microbiota. Among them, the combination of betaine and TMAO had the best effect.

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Mulberry leaf (Morus alba L.) is used as a traditional medicine and potential health food to treat various metabolic diseases, such as hypertension, diabetes, and hyperlipidemia. However, we sought the mechanisms by which functional components of mulberry leaves mediate diabetic steatohepatitis. We applied an in vitro model of HepG2 cells induced by glucolipotoxicity and evaluated the effects of MLE and its major components nCGA, Crp, and CGA. The results showed that MLE and nCGA reduced liver fat accumulation by inhibiting SREBP-1/FASN, SREBP-2/HMG-CoAR, and activating PPARα/CPT-1. Additionally, MLE and nCGA decreased inflammatory responses associated with NF-κB, TNF-α, and IL-6 to alleviate steatohepatitis. Furthermore, we showed that MLE and nCGA exerted anti-glucolipotoxicity effects by downregulating miR-34a, thus activating SIRT1/AMPK signaling, and subsequently suppressing hepatic lipid accumulation.

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As a traditional Chinese medicine, licorice is often used in functional foods for its health benefits. However, the role of gut microbiota in the efficacy of licorice has not yet been fully elucidated. We hypothesized that the involvement of intestinal flora may be a key link in licorice ethanol extract (LEE)-induced health benefits. The aim of this study was to investigate whether LEE improves hepatic lipid accumulation in obese mice fed a high-fat diet (HFD) and whether the gut microbiota plays a key role in LEE treatment. Male C57BL/6J mice were fed HFD for liver fat accumulation and then treated with LEE. The same experiments were later performed using pseudo-sterile mice to verify the importance of gut flora. Supplementation with LEE improved the obesity profile, lipid profile and liver fat accumulation in HFD mice. In addition, LEE treatment improved intestinal flora dysbiosis caused by HFD in mice, as evidenced by a decrease in the percentage of Firmicutes/Bacteroidetes and an increase in the abundance of known anti-obesity-related bacteria. However, LEE failed to exhibit a therapeutic effect in pseudo-sterile mice. The results of the cellular assay showed that glycyrrhetic acid (GA), the main conversion product of glycyrrhizin (GL), was more effective in reducing fat accumulation and intracellular TG content in hepatocytes compared to GL. In conclusion, our data suggest that LEE attenuates obesity and hepatic fat accumulation in HFD mice, which may be associated with modulating the composition of gut microbiota and the conversion of LLE by the intestinal flora.

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OBJECTIVE: Pituitary adenylate cyclase-activating polypeptide (PACAP) was reported to attenuate hepatic lipid accumulation in overnutrition-related metabolic disorder, mediated by up-regulation of fas apoptosis inhibitory molecule (FAIM). However, how PACAP regulates FAIM in metabolic tissues remains to be addressed. Here we investigated the underlying mechanism on the role of PACAP in ameliorating metabolic disorder and examined the potential therapeutic effects of PACAP in preventing the progression of metabolic associated fatty liver disease (MAFLD). METHODS: Mouse models with MAFLD induced by high-fat diet were employed. Different doses of PACAP were intraperitoneally administrated. Western blot, luciferase assay, lentiviral-mediated gene manipulations and animal metabolic phenotyping analysis were performed to explore the signaling pathway involved in PACAP function. RESULTS: PACAP ameliorated the excessive hepatic lipid accumulation and inhibited lipogenesis in HFD-fed C57BL/6J mice. Mechanistically, PACAP activated the FAIM-AMPK-IRß axis to inhibit the expression of lipid synthesis genes, and FAIM mediated the effects of PACAP. FAIM suppression via lentiviral-mediated shRNA inhibited the activation of AMPK, whereas FAIM overexpression promoted AMPK activation. PACAP increased the promoter activity of FAIM gene through activating PKA-CREB signaling pathway. CONCLUSION: Our work demonstrated that the administration of PACAP represented a feasible approach for treating hepatic lipid accumulation in MAFLD. The findings reveal the molecular mechanism that PACAP increase FAIM expression and activates the FAIM/AMPK/IRß signaling axis, thus inhibits lipogenesis to mediate its beneficial effects.

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CONTEXT: Shen-Shi-Jiang-Zhuo formula (SSJZF) exhibits a definite curative effect in the clinical treatment of non-alcoholic fatty liver disease (NAFLD). OBJECTIVE: To explore the therapeutic effect and mechanism of SSJZF on NAFLD. MATERIALS AND METHODS: Sprague Dawley rats were randomly divided into control, NAFLD, positive drug (12 mg/kg/day), SSJZF high-dose (200 mg/kg/day), SSJZF middle-dose (100 mg/kg/day), and SSJZF low-dose (50 mg/kg/day) groups. After daily intragastric administration of NAFLD rats for 8 weeks, lipid metabolism and hepatic fibrosis were evaluated by biochemical indices and histopathology. Then we uncovered the main active compounds and mechanism of SSJZF against NAFLD by integrating RNA-sequencing and network pharmacology, and PI3K/AKT pathway activity was verified by western blot. RESULTS: High dose SSJZF had the best inhibitory effect on hepatic lipid accumulation and fibrosis in rats with NAFLD, which significantly down-regulated total triglycerides (58%), cholesterol (62%), aspartate aminotransferase (57%), alanine aminotransferase (41%) andγ-glutamyl transpeptidase (36%), as well as the expression of ACC (5.3-fold), FAS (12.1-fold), SREBP1C (2.3-fold), and CD36 (4.4-fold), and significantly reduced collagen deposition (67%). Then we identified 23 compounds of SSJZF that acted on 25 key therapeutic targets of NAFLD by integrating RNA-sequencing and network pharmacology. Finally, we also confirmed that high dose SSJZF increased p-PI3K/PI3K (1.6-fold) and p-AKT/AKT (1.6-fold) in NAFLD rats. DISCUSSION AND CONCLUSION: We found for first time that SSJZF improved NAFLD in rats by activating the PI3K/Akt pathway. These findings provide scientific support for SSJZF in the clinical treatment of NAFLD and contribute to the development of new NAFLD drugs.

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