Hepatic Lipogenesis Research Articles

MicroRNA-206-3p suppresses hepatic lipogenesis and cholesterol synthesis while driving cholesterol efflux.

Hepatosteatosis, hypertriglyceridemia, and hypertriglyceridemia are interconnected metabolic disorders. This study is designed to characterize how microRNA-206-3p (miR-206) simultaneously prevents de novo lipogenesis (DNL), cholesterol synthesis, and VLDL production in hepatocytes while promoting cholesterol efflux in macrophages. MiR-206 levels were reduced in hepatocytes and macrophages of mice subjected to a high-fat, high-cholesterol diet (HFHC). A negative feedback between LXRα (liver X receptor) and miR-206 is formed to maintain high LXRα and low miR-206 in hepatocytes. Systemic administration of miR-206 alleviated hepatosteatosis, hypertriglyceridemia and hypercholesterolemia in mice. A significant reduction in LDL-cholesterol and VLDL-cholesterol but unaltered HDL-cholesterol was observed in miR-206-treated mice. Mirroring these findings, miR-206 reprogrammed the transcriptome of hepatocytes towards inhibition of DNL, cholesterol synthesis, and assembly and secretion of VLDL. In macrophages, miR-206 activated expression of genes regulating cholesterol efflux. Hepatocyte-specific expression of miR-206 reduced hepatic and circulating triglycerides and cholesterol as well as VLDL production, while transplantation of macrophages bearing miR-206 facilitated cholesterol efflux. Mechanistically, miR-206 directly targeted Lxrα and Hmgcr in hepatocytes but facilitated expression of Lxrα in macrophages by targeting macrophage-specific TRPS1 (tricho-rhino-phalangeal syndrome 1), a transcription repressor of Lxrα. By targeting Hmgcr and Lxrα, miR-206 inhibited DNL, VLDL production and cholesterol synthesis in hepatocytes, whereas it drove cholesterol efflux by activating the TRPS1-LXRα axis. MiR-206, through differentially modulating LXRα signaling in hepatocytes and macrophages, inhibits DNL, promotes cholesterol efflux, and concurrently hinders cholesterol synthesis and VLDL production. MiR-206 simulates the functions of lipid-lowering medications, statins and LXRα agonists.

Broodstock nutritional programming differentially affects the hepatic transcriptome and genome-wide DNA methylome of farmed gilthead sea bream (Sparus aurata) depending on genetic background

BackgroundBroodstock nutritional programming improves the offspring utilization of plant-based diets in gilthead sea bream through changes in hepatic metabolism. Attention was initially focused on fatty acid desaturases, but it can involve a wide range of processes that remain largely unexplored. How all this can be driven by a different genetic background is hardly underlined, and the present study aimed to assess how broodstock nutrition affects differentially the transcriptome and genome-wide DNA methylome of reference and genetically selected fish within the PROGENSA® selection program.ResultsAfter the stimulus phase with a low fish oil diet, two offspring subsets of each genetic background received a control or a FUTURE-based diet. This highlighted a different hepatic transcriptome (RNA-seq) and genome-wide DNA methylation (MBD-seq) pattern depending on the genetic background. The number of differentially expressed transcripts following the challenge phase varied from 323 in reference fish to 2,009 in genetically selected fish. The number of discriminant transcripts, and associated enriched functions, were also markedly higher in selected fish. Moreover, correlation analysis depicted a hyper-methylated and down-regulated gene expression state in selected fish with the FUTURE diet, whereas the opposite pattern appeared in reference fish. After filtering for highly represented functions in selected fish, 115 epigenetic markers were retrieved in this group. Among them, lipid metabolism genes (23) were the most reactive following ordering by fold-change in expression, rendering a final list of 10 top markers with a key role on hepatic lipogenesis and fatty acid metabolism (cd36, pitpna, cidea, fasn, g6pd, lipt1, scd1a, acsbg2, acsl14, acsbg2).ConclusionsGene expression profiles and methylation signatures were dependent on genetic background in our experimental model. Such assumption affected the magnitude, but also the type and direction of change. Thus, the resulting epigenetic clock of reference fish might depict an older phenotype with a lower methylation for the epigenetically responsive genes with a negative methylation-expression pattern. Therefore, epigenetic markers will be specific of each genetic lineage, serving the broodstock programming in our selected fish to prevent and mitigate later in life the risk of hepatic steatosis through changes in hepatic lipogenesis and fatty acid metabolism.

Unsaponifiable Matter from Wheat Bran Cultivated in Korea Inhibits Hepatic Lipogenesis by Activating AMPK Pathway.

Unsaponifiable matter (USM) from wheat bran, a by-product obtained from wheat milling, is abundant in health-promoting compounds such as phytosterols, tocopherols, policosanols, and alkylresorcinols. This study aimed to examine the effects of USM from the wheat bran of normal and waxy type wheat, Saekeumkang (SKK) and Shinmichal (SMC), on hepatic lipid accumulation in free fatty acid (FFA)-induced hepatocytes and to investigate the cellular mechanism. The total phytochemical contents were 46.562 g/100 g USM and 38.130 g/100 g USM from SKK and SMC, respectively. FFA treatment increased intracellular lipid accumulation by approximately 260% compared to the control group; however, treatment with USM from SKK and SMC significantly attenuated lipid accumulation in the hepatocytes in a dose-dependent manner. Moreover, USM downregulated the expression of lipogenic factors such as fatty acid synthase and sterol regulatory-element-binding protein 1c by approximately 40% compared to the FFA treatment group. Treatment with USM promoted lipolysis and positively regulated the expression of the proteins involved in β-oxidation, including peroxisome proliferator-activated receptor α and its downstream protein, carnitine palmitoyltransferase 1A. Moreover, the blockade of AMPK activation significantly abolished the inhibitory effects of USM on hepatic lipid accumulation. These results indicated that the USM from both SKK and SMC can alleviate lipid accumulation in hepatocytes in an AMPK-dependent manner. Therefore, USM from wheat bran may be useful as a therapeutic intervention for treating metabolic-dysfunction-associated fatty liver disease.

Olfactomedin 4 deletion exacerbates nonalcoholic fatty liver disease through P62-dependent mitophagy in mice.

Olfactomedin 4 (OLFM4) is a glycoprotein that is related to obesity and insulin resistance. This study aims to investigate the role and mechanisms of OLFM4 in nonalcoholic fatty liver disease (NAFLD). OLFM4 expression levels were significantly increased in liver samples from NAFLD patients and in cellular and mouse models of NAFLD. Cell lines deficient in or overexpressing OLFM4 and Olfm4-/- mice were established to study its role in NAFLD. OLFM4 deficiency significantly aggravated diet-induced hepatic steatosis and inflammation, while re-expression of OLFM4 ameliorated diet-induced hepatic steatosis and inflammation in mice. Mechanistically, OLFM4 deficiency disrupted mitochondrial structure and decreased mitophagy in hepatocytes, thereby aggravating hepatic lipogenesis, inflammation, and insulin resistance. Moreover, OLFM4 directly interacted with P62, and OLFM4 deficiency decreased mitophagy in both cellular and mouse models of NAFLD through a P62-dependent mechanism. We also show that blocking the P62-ZZ-domain using XRK3F2 prevented diet-induced NAFLD in Olfm4-/- mice. OLFM4 is significantly upregulated in NAFLD, and OLFM4 deletion exacerbates NAFLD through P62-dependent mitophagy.

Stimuli-Responsive Pressure-Strain Sensor-Based Conductive Hydrogel for Alleviated Non-alcoholic Fatty Liver Disease by Scavenging Reactive Oxygen Species in Adipose Tissue.

A visible light- and reactive oxygen species (ROS)-responsive pressure/strain sensor based on carbon dot (CD)-loaded conductive hydrogel was developed for detecting high-fat diet (HFD) and preventing the risk of non-alcoholic fatty liver disease. The designed nanoparticle consisted of a diselenide polymer dot (dsPD) loaded with a visible light-responsive CD to form dsPD@CD (DSCD). The influence of visible light irradiation and ROS on DSCD facilitated the electron transport, enhancing the conductivity of DSCD-embedded hydrogel (DSCD hydrogel) from 1.3 to 35.9 mS/m. Alternatively, the tensile modulus of the DSCD hydrogel enhanced to 223% after light-induced ROS treatment, which simultaneously impacted the capacitive response (120%). The hydrogel implantation into inguinal white adipose tissue of HFD mice showed 82% higher conductivity and 83% enhanced pressure sensing response to HFD-generated high ROS levels compared with the normal diet-fed mice. Additionally, the ROS scavenging activity of DSCD hydrogel was confirmed by the downregulation of ROS-responsive genes, such as Sod2, Nrf2, and catalase (Cat) in murine primary hepatocytes isolated from fatty liver-induced mice. In addition, in vivo animal studies also confirmed the suppression of hepatic lipogenesis, as shown by decreased Pparγ and Fasn expression and hypertrophy of adipocytes in HFD mice. The distinguishable real-time wireless resistance response observed with pressure sensing indicates the potential application of the device for monitoring the risk of non-alcoholic fatty liver disease. STATEMENT OF SIGNIFICANCE: : A visible-light-induced ROS-responsive carbon dot-loaded conductive hydrogel was developed for the detection of HFD-induced alterations in ROS levels by evaluating the conductivity and electrochemical responses with applied pressure/strain. The implanted hydrogel facilitates the recovery of the inflated adipocytes induced by NAFLD, which reduces fat accumulation in the liver, preventing the risk of NAFLD. Real-time detection based on the resistance response during local compression of the hydrogel is possibly performed utilizing a wireless sensing device, demonstrating the ease of NAFLD monitoring.

FoxO1 as a tissue-specific therapeutic target for type 2 diabetes.

Forkhead box O (FoxO) proteins are transcription factors that mediate many aspects of physiology and thus have been targeted as therapeutics for several diseases including metabolic disorders such as type 2 diabetes mellitus (T2D). The role of FoxO1 in metabolism has been well studied, but recently FoxO1's potential for diabetes prevention and therapy has been debated. For example, studies have shown that increased FoxO1 activity in certain tissue types contributes to T2D pathology, symptoms, and comorbidities, yet in other tissue types elevated FoxO1 has been reported to alleviate symptoms associated with diabetes. Furthermore, studies have reported opposite effects of active FoxO1 in the same tissue type. For example, in the liver, FoxO1 contributes to T2D by increasing hepatic glucose production. However, FoxO1 has been shown to either increase or decrease hepatic lipogenesis as well as adipogenesis in white adipose tissue. In skeletal muscle, FoxO1 reduces glucose uptake and oxidation, promotes lipid uptake and oxidation, and increases muscle atrophy. While many studies show that FoxO1 lowers pancreatic insulin production and secretion, others show the opposite, especially in response to oxidative stress and inflammation. Elevated FoxO1 in the hypothalamus increases the risk of developing T2D. However, increased FoxO1 may mitigate Alzheimer's disease, a neurodegenerative disease strongly associated with T2D. Conversely, accumulating evidence implicates increased FoxO1 with Parkinson's disease pathogenesis. Here we review FoxO1's actions in T2D conditions in metabolic tissues that abundantly express FoxO1 and highlight some of the current studies targeting FoxO1 for T2D treatment.

Towards sustainable aquaculture: Assessing polychaete meal (Alitta virens) as an effective fishmeal alternative in European seabass (Dicentrarchus labrax) diets

In recent years, the pursuit of sustainable aquaculture practices has focused on alternatives to fisheries-derived ingredients, to avoid economic and environmental unsustainability. Low-trophic organisms, such as polychaetes, could be a suitable alternative to fishmeal due to their high protein content. This study aimed to investigate the feasibility of replacing fishmeal with the polychaete meal (Alitta virens; PM) in diets for European seabass (Dicentrarchus labrax; Wi, ∼14.5 g). Four isoproteic (51% dry matter, DM) and isolipidic (17% DM) diets were fed to seabass juveniles: a fishmeal-based diet (FM) and three experimental diets with PM at inclusion levels of 2.5% (PM2.5), 5% (PM5), and 10% (PM10), replacing 10%, 20% and 40% of fishmeal, respectively. After 93 days of feeding, the effects of the PM on growth, digestibility, nutrient utilization, plasma metabolites, liver lipogenic activity, and anterior intestine histomorphology were analyzed. The environmental impact of all diets was also assessed. All diets were well-accepted by the fish, and promoted equal growth performance, ensuring high feed efficiency. The muscle EPA + DHA content in all dietary groups exceeded the recommended levels for human consumption. Hepatic lipogenesis and plasma triglyceride and non-esterified fatty acids (NEFA) levels were increased in fish fed PM2.5, suggesting that the PM promoted alterations in lipid metabolism, especially at low inclusion levels. PM2.5 also seemed to enhance the absorption capacity of the anterior intestine by increasing villus length and goblet cells number/area, albeit without impacting nutrient digestibility and growth performance. Furthermore, copper digestibility increased with higher levels of PM inclusion. The assessment of environmental sustainability indicated that the experimental diets incorporating PM present a more sustainable option compared to fishmeal. Overall, this study demonstrated that PM can serve as a sustainable alternative to fishmeal, replacing it by up to 40%, without compromising European seabass growth and nutrient utilization, while guaranteeing a high nutritional quality fillet for human consumption. The best environmental performance could be achieved with a diet comprising 5% to 10% (w/w) PM content. However, further research is needed to understand the underlying mechanisms of PM's effects on intermediary metabolism and its potential as a functional ingredient.

The GR-KLF15 axis promotes suppression of hepatic lipogenesis during fasting.

Fasting leads to many physiological changes in peripheral tissues, including the liver, where suppression of de novo lipogenesis through inhibition of sterol regulatory element-binding protein 1 (SREBP-1) expression and/or activity is a key adaptation to preserve glucose for maintenance of blood glucose levels. Yoshinori Takeuchi and colleagues provide novel mechanistic insights into the regulation of SREBP-1 expression during fasting and highlight the importance of the hypothalamic-pituitary-adrenal axis and, particularly, glucocorticoid-induced binding of the glucocorticoid receptor to enhancer regions of the KLF15 (Kruppel-like factor 15) gene as a novel mechanism underlying the suppression of SREBP-1 during fasting.

Non-Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is characterized by the buildup of fat in the liver, and it is not caused by excessive alcohol consumption. NAFLD is highly prevalent, affecting approximately 30% of the population in developed countries and around 10% in developing nations. As a result, NAFLD has become the most prevalent liver condition worldwide.
 The development of NAFLD is closely linked to insulin resistance, making it common among individuals who have central obesity or diabetes. Insulin resistance and excess body fat contribute to a higher influx of lipids into the liver and an increased production of new fats within the liver, known as de novo hepatic lipogenesis. These processes ultimately lead to the accumulation of triglycerides in the liver, a characteristic feature of NAFLD.
 NAFLD is closely associated with components of the metabolic syndrome, and individuals with type 2 diabetes have an increased risk of developing cirrhosis and its related complications. While cardiovascular disease and extra hepatic malignancy are the leading causes of death in people with NAFLD, the presence of advanced liver fibrosis is a significant indicator of liver-related outcomes and overall mortality. Non-invasive tests that combine various methods can be used to assess the extent of liver fibrosis. Patients diagnosed with cirrhosis should undergo screenings for hepatocellular carcinoma (a type of liver cancer) and esophageal varices. Currently, there are no approved therapies for NAFLD; however, there are several drugs in advanced stages of development that show promise for future treatment options.
 Keywords: Non-alcoholic fatty liver disease, Weight management, Bariatric surgery, Metabolic surgery, Conservative therapy.

Dose-dependent effects of rumen-protected choline on hepatic metabolism during induction of fatty liver in dry pregnant dairy cows.

Objectives were to determine the effects of supplementing increasing amounts of choline ion on hepatic composition and mRNA abundance in pregnant dry cows subjected to a fatty liver induction protocol. Holstein cows (35 primiparous and 41 multiparous) at mean (± standard deviation) of 211 ± 9.9 days of gestation were blocked by body condition (3.59 ± 0.33) and assigned to receive 0, 6.45, 12.90, 19.35, and 25.80 g/day of choline ion as rumen-protected choline (RPC) as a top-dress for 14 days. Cows were fed for ad libitum intake on days 1 to 5 and restricted to 30% of the required net energy for lactation from days 6 to 14 of the experiment. Hepatic tissue was sampled on days 5 and 14 and analyzed for concentrations of triacylglycerol and glycogen, and mRNA abundance was investigated. Orthogonal contrasts evaluated the effects of supplementing RPC (0 g/day vs. rest), and the linear, quadratic, and cubic effects of increasing intake of choline ion from 6.45 to 25.80 g/day. Results are depicted in sequence of treatments from 0 to 25.8. During feed restriction, RPC reduced the concentration of hepatic triacylglycerol by 28.5% and increased that of glycogen by 26.1%, and the effect of increasing RPC intake on triacylglycerol was linear (6.67 vs. 5.45 vs. 4.68 vs. 5.13 vs. 3.81 ± 0.92% wet-basis). Feeding RPC during feed restriction increased abundance of transcripts involved in choline metabolism (CHKA, PLD1), synthesis of apolipoprotein-B100 (APOB100), and antioxidant activity (GPX3), and decreased the abundance of transcripts involved in hepatic lipogenesis (DGAT2, SREBF1) and acute phase response (SAA3). Most effects were linear with amount of choline fed. Changes in hepatic mRNA abundance followed a pattern of reduced lipogenesis and enhanced lipids export, which help explain the reduced hepatic triacylglycerol content in cows fed RPC. Choline exerts lipotropic effects in dairy cows by altering transcript pathways linked to hepatic lipids metabolism.

THU335 Hyperinsulinemia Is Associated With An Atherogenic Lipoprotein Profile In Humans With Selective Insulin Resistance And An Atheroprotective Profile In Humans With Non-selective Insulin Resistance

Abstract Disclosure: D. Walzer: None. M. Lightbourne: None. M. Walter: None. Y. Dai: None. R.D. Shamburek: None. R.J. Brown: None. Insulin resistance (IR), a major risk factor for cardiovascular disease (CVD), leads to hyperglycemia and dyslipidemia. In obesity-associated IR, dyslipidemia attributed to increased stimulation of hepatic lipogenesis by insulin, whereas IR in glucoregulatory pathways leads to hyperglycemia. This dichotomy in insulin signaling pathways is termed selective IR. Lipodystrophy syndromes (LD) are rare conditions of severe, selective IR in which, like obesity, hyperinsulinemia with excess insulin receptor signaling is thought to cause high triglycerides (TG) & low HDL. By contrast, in the rare condition of insulin receptor pathogenic variants (INSR) (nonselective IR) lack of insulin signaling through its receptor despite hyperinsulinemia leads to low TG and high HDL. Rodents with hepatic INSR k/o have an atherogenic lipid profile, but the lipoprotein profile in humans with INSR is unknown. Factors influencing atherogenicity of lipoprotein particles, including cholesteryl ester transfer protein (CETP) activity and adiponectin, have not been explored in these human models of severe selective vs. non-selective IR. We characterized atherogenicity of lipoprotein particles and factors influencing these particles in subjects with LD matched 2:1 with subjects with INSR based on age and sex. All subjects had fasting lipoprotein profiles by NMR spectroscopy, apolipoproteins AI (ApoI) and B (ApoB), total adiponectin by ELISA, and CETP activity by fluorometric assay. Subjects with LD (N=24, 75% female; 8 generalized, 16 partial) had a more atherogenic lipoprotein profile vs INSR (N=12, 50% female; 6 homozygous, 6 heterozygous), with 45-fold higher large TRLP, 20-fold higher medium TRLP, 15-fold higher very small TRLP (representing IDL), 3-fold higher small LDLP, 4-fold lower large HDLP, 1.7—fold higher ApoB, and 1.4—fold lower ApoAI (p <0.05 for all). CETP activity was comparable in INSR and LD. Adiponectin was 5.9- fold lower in LD vs INSR (p <0.0001). Among all subjects, adiponectin was positively associated with HDL-C, large HDLP, HDL size, and ApoA-I (p=0.001), and negatively correlated with TRLP number & size, small LDLP, and very small TRLP (p<0.0001). Selective IR in LD is associated with an atherogenic lipoprotein particle profile. By contrast, non-selective IR in INSR is associated with an atheroprotective profile, which differs from rodent models. These divergent lipid phenotypes are not explained by different CETP activity. Although preclinical studies suggest that adiponectin promotes a favorable lipoprotein profile consistent with our observed associations, a causal link in humans is not supported by Mendelian randomization studies or rare ADIPOQ gene deletions. Overall, these findings suggest a key role of selective insulin resistance in the development of an atherogenic lipid profile. Further studies are needed to see if this profile leads to increased CVD risk. Presentation: Thursday, June 15, 2023

Tianhuang formula ameliorates non-alcoholic fatty liver diseases in type 2 diabetic mice through CRLS1-ATF3/ChREBP pathway

ObjectiveTianhuang Formula (THF) is a hospital formula summarized by Professor Jiao Guo's 30 years of clinical experience. Some studies have shown that it can alleviate dyslipidemia in the body. The purpose of this study is to confirm whether THF can improve non-alcoholic fatty liver diseases (NAFLD) in type 2 diabetic mice induced by high-fat diet (HFD)/streptomycin (STZ) and to clarify its potential mechanism. MethodsAfter induction of diabetes, mice were administrated with THF (60 ​mg/kg or 120 ​mg/kg) once daily for 10 weeks. Blood glucose (FBG), glucose tolerance, and insulin resistance (IR) were assayed by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Blood lipids, alanine transaminase (ALT), and aspartate transaminases (AST) were detected. Serum fasting insulin (INS) and adiponectin (APN) levels were measured using ELISA. Histological changes in liver and pancreatic islets were observed by H&E staining, followed by Oil Red O staining for liver lipid quantification and periodic acid-Schiff (PAS) staining to detect glycogen accumulation. Western blotting detected the levels of fatty cardiolipin synthase 1 (CRLS1), transcription factor activator 3 (ATF3), and carbohydrate-responsive element binding protein (ChREBP) in the liver. The mRNA transcripts of hepatic inflammatory factors, lipogenesis and lipolysis-related genes, and gluconeogenic enzyme-phosphoenolpyruvate carboxykinase (PEPCK), CRLS1, ATF3, and ChREBP mRNA levels were evaluated by RT-qPCR. ResultsTHF restored impaired glucose tolerance and insulin resistance, respectively. There was an improvement in HFD/STZ-induced liver and islet damage, high serum HDL-C and ANP levels, and a significant decrease in FBG, total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), FFA, INS, ALT, and AST, and lipid droplet counts in the T2DM mice treated with THF. CREBBP binding protein ATF3 mediated the insulin resistance signaling pathway, which regulated glucose and lipid metabolism in the liver. THF upregulated CRLS1, and ChREBP downregulated the expression of downstream ATF3 in the liver. RT-qPCR analysis also systemically indicated that THF suppressed the pathway and key regulators related to inflammation, lipid accumulation, and gluconeogenesis. ConclusionOur findings demonstrated that THF ameliorated lipid profile and attenuated liver steatosis in T2DM mice through CRLS1-ATF3/ChREBP pathway activation.

Identification of novel SCD1 inhibitor alleviates nonalcoholic fatty liver disease: critical role of liver-adipose axis

Due to the complexity and incomplete understanding of the crosstalk between liver and adipose tissue, especially the processes of hepatic lipogenesis and adipogenic differentiation, there are currently no effective drugs for the treatment of nonalcoholic fatty liver disease (NAFLD). Stearoyl-coenzyme A desaturase 1 (SCD1), which is abundantly expressed in liver and adipose tissue, may mediate the cross-talk between liver and adipose tissue. Thus, it is essential to develop specific SCD1 inhibitors that target the liver-adipose axis. Herein, we identified a novel SCD1 inhibitor, E6446, through a high-throughput virtual screen. E6646 significantly inhibited adipogenic differentiation and hepatic lipogenesis via SCD1-ATF3 signaling. The SPR results showed that E6446 had a strong interaction ability with SCD1 (KD:4.61 μM). Additionally, E6646 significantly decreased hepatic steatosis, hepatic lipid droplet accumulation and insulin resistance in high-fat diet (HFD)-fed mice. Taken together, our findings not only suggest that E6446 can serve as a new, safe and highly effective anti-NAFLD agent for future clinical use but also provide a molecular basis for the future development of SCD1 inhibitors that inhibit both adipogenic differentiation and hepatic lipogenesis.-_fLbJcbqbtKciFUEE_QdNVideo

GR-KLF15 pathway controls hepatic lipogenesis during fasting.

During periods of fasting, the body undergoes a metabolic shift from carbohydrate utilization to the use of fats and ketones as an energy source, as well as the inhibition of de novo lipogenesis and the initiation of gluconeogenesis in the liver. The transcription factor sterol regulatory element-binding protein-1 (SREBP-1), which plays a critical role in the regulation of lipogenesis, is suppressed during fasting, resulting in the suppression of hepatic lipogenesis. We previously demonstrated that the interaction of fasting-induced Kruppel-like factor 15 (KLF15) with liver X receptor serves as the essential mechanism for the nutritional regulation of SREBP-1 expression. However, the underlying mechanisms of KLF15 induction during fasting remain unclear. In this study, we show that the glucocorticoid receptor (GR) regulates the hepatic expression of KLF15 and, subsequently, lipogenesis through the KLF15-SREBP-1 pathway during fasting. KLF15 is necessary for the suppression of SREBP-1 by GR, as demonstrated through experiments using KLF15 knockout mice. Additionally, we show that GR is involved in the fasting response, with heightened binding to the KLF15 enhancer. It has been widely known that the hypothalamic-pituitary-adrenal (HPA) axis regulates the secretion of glucocorticoids and plays a significant role in the metabolic response to undernutrition. These findings demonstrate the importance of the HPA-axis-regulated GR-KLF15 pathway in the regulation of lipid metabolism in the liver during fasting.

Black mulberry extract inhibits hepatic adipogenesis through AMPK/mTOR signaling pathway in T2DM mice

Ethnopharmacological relevanceBlack mulberry (Morus nigra L.) is an ancient dual-use plant resource for medicine and food. It is widely used in Uyghur folklore for hypoglycemic treatment and is a folkloric plant medicine with regional characteristics. However, the mechanism of Morus nigra L. treatment in diabetes mellitus has not been fully understood, especially from the perspective of hepatic lipid accumulation is less reported. Objective of this studyThis study was to explore the potential of Morus nigra L. fruit ethyl acetate extract (MNF-EA) to reduce blood sugar levels by preventing the production of hepatic lipogenesis and to provide more evidence for the use of MNF-EA as an adjuvant therapy for type 2 diabetes mellitus (T2DM). Materials and methodsIn this study, the chemical composition of MNF-EA was first analyzed and characterized using UPLC-Q-TOF-MS technique. A series of in vitro studies were performed with HepG2-IR cells and oleic acid (OA)-induced HepG2 cells, including MTT assay, glucose uptake assay, oil red O staining and Western blot analysis. The STZ-HFD co-induced T2DM mice were employed for in vivo research, including physical indices, biochemical analysis, histopathological examination, and Western blot analysis. ResultsThe 19 compounds in MNF-EA were identified by UPLC-Q-TOF-MS technique. Insulin resistance (IR) and lipid droplet accumulation in HepG2 cells were greatly improved by MNF-EA treatment, which had no appreciable side effects at the dosage used. In T2DM mice, MNF-EA decreased fasting blood glucose (FBG), saved body weight, and significantly improved oral glucose tolerance (OGTT) and IR status. In addition, MNF-EA treatment also improved lipid metabolism disorders and liver function in T2DM mice. Histopathological sections showed that MNF-EA treatment reduced hepatic steatosis. Mechanistic studies suggest that MNF-EA acted through the AMPK/mTOR pathway. ConclusionsThese results suggest that MNF-EA has great potential to reverse the metabolic abnormalities associated with T2DM by regulating the AMPK/mTOR signaling pathway. Therefore, we believe that MNF is a promising medicinal and food-homologous agent to improve T2DM.

Bempedoic Acid Unveils Therapeutic Potential in Non-Alcoholic Fatty Liver Disease: Suppression of the Hepatic PXR-SLC13A5/ACLY Signaling Axis.

The hepatic SLC13A5/SLC25A1-ATP-dependent citrate lyase (ACLY) signaling pathway, responsible for maintaining the citrate homeostasis, plays a crucial role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Bempedoic acid (BA), an ACLY inhibitor commonly used for managing hypercholesterolemia, has shown promising results in addressing hepatic steatosis. This study aimed to elucidate the intricate relationships in processes of hepatic lipogenesis among SLC13A5, SLC25A1, and ACLY and to examine the therapeutic potential of BA in NAFLD, providing insights into its underlying mechanism. In murine primary hepatocytes and HepG2 cells, the silencing or pharmacological inhibition of SLC25A1/ACLY resulted in significant upregulation of SLC13A5 transcription and activity. This increase in SLC13A5 activity subsequently led to enhanced lipogenesis, indicating a compensatory role of SLC13A5 when the SLC25A1/ACLY pathway was inhibited. However, BA effectively counteracted this upregulation, reduced lipid accumulation, and ameliorated various biomarkers of NAFLD. The disease-modifying effects of BA were further confirmed in NAFLD mice. Mechanistic investigations revealed that BA could reverse the elevated transcription levels of SLC13A5 and ACLY, and the subsequent lipogenesis induced by PXR activation in vitro and in vivo. Importantly, this effect was diminished when PXR was knocked down, suggesting the involvement of the hepatic PXR-SLC13A5/ACLY signaling axis in the mechanism of BA action. In conclusion, SLC13A5-mediated extracellular citrate influx emerges as an alternative pathway to SLC25A1/ACLY in the regulation of lipogenesis in hepatocytes, BA exhibits therapeutic potential in NAFLD by suppressing the hepatic PXR-SLC13A5/ACLY signaling axis, while PXR, a key regulator in drug metabolism may be involved in the pathogenesis of NAFLD. SIGNIFICANCE STATEMENT: This work describes that bempedoic acid, an ATP-dependent citrate lyase (ACLY) inhibitor, ameliorates hepatic lipid accumulation and various hallmarks of non-alcoholic fatty liver disease. Suppression of hepatic SLC25A1-ACLY pathway upregulates SLC13A5 transcription, which in turn activates extracellular citrate influx and the subsequent DNL. Whereas in hepatocytes or the liver tissue challenged with high energy intake, bempedoic acid reverses compensatory activation of SLC13A5 via modulating the hepatic PXR-SLC13A5/ACLY axis, thereby simultaneously downregulating SLC13A5 and ACLY.

Beyond fish oil: Assessing the implications of alternative dietary lipid sources for turbot (Scophthalmus maximus) on growth, nutrient utilization and muscle quality

Various combinations of alternative marine lipid sources were evaluated for their potential to replace commercially available fish oil, specifically sardine oil (SO), in turbot (Scophthalmus maximus). A commercially based diet was used as a control (CTRL) containing sardine oil (7.0%) and rapeseed oil (RO; 3.8%) as the main lipid sources, providing 1.9% EPA + DHA. A positive control (SARDINE) was also included, which used SO as the sole lipid source to provide 2.6% EPA + DHA. Two other diets were formulated to target approximately the same levels of EPA + DHA as the positive control: ALGA (2.7% algae oil, 5.4% SO, and 2.7% RO), and ALGAMIX (a blend of 2.0% micro and macro algae biomass, 9.5% SO, and 0.7% salmon oil, a by-product of the salmon industry). SO was completely replaced in two alternative diets, ALT1 and ALT2, by different ratios of salmon and algae oils: 8.0/2.9 and 6.0/4.9%, providing 2.0% and 2.8% EPA + DHA, respectively. In these alternative diets, 30% of the fish meal was also replaced, by Tenebrio molitor meal and a single-cell protein concentrate from Corynebacterium glutamicum. After 75 days of feeding, all diets were equally well-accepted by the fish, and no significant differences were found in feed efficiency, growth performance, and somatic indexes. All fish had similar muscle EPA + DHA values, but only the ALGAMIX group exceeded the European Food Safety Authority (EFSA) recommended EPA + DHA levels for human daily consumption. Hepatic lipogenesis was decreased in fish fed with higher levels of EPA + DHA, suggesting that increased n-3 LC-PUFA negatively affects lipid metabolism. Additionally, the mixture of algae oil, sardine oil, and rapeseed oil (ALGA diet) showed potential for improving muscle antioxidant capacity. Overall, this study showed that combining expensive sources of n-3 long-chain polyunsaturated fatty acids (LC-PUFA) with less expensive oils, such as salmon by-product oil or vegetable oils, may be a viable cost-efficient strategy for replacing SO in diets for turbot. This can be achieved without compromising growth and while ensuring high flesh n-3 LC-PUFA content and improving its antioxidant potential.

Ufmylation on UFBP1 alleviates non-alcoholic fatty liver disease by modulating hepatic endoplasmic reticulum stress

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease characterized by lipid accumulation and endoplasmic reticulum (ER) stress, while effective therapies targeting the specific characteristics of NAFLD are limited. Ufmylation is a newly found post-translational modification process that involves the attachment of the Ubiquitin-fold modifier 1 (UFM1) protein to its substrates via ufmylation modification system. Ufmylation regulates ER stress via modifying UFM1 binding protein 1 (UFBP1), suggesting a potential role for ufmylation in NAFLD pathogenesis. However, the precise role of ufmylation in NAFLD remains unclear. Herein, we aim to elucidate the impact of ufmylation on UFBP1 in NAFLD and explore the underlying mechanisms involved. We observed increased expression of UFM1-conjugated proteins and ufmylation modification system components in livers with steatosis derived from NAFLD patients and NAFLD models. Upregulation of ufmylation on hepatic proteins appeared to be an adaptive response to hepatic ER stress in NAFLD. In vitro, knocking down UFBP1 resulted in increased lipid accumulation and lipogenesis in hepatocytes treated with free fatty acids (FFA), which could be rescued by wild-type UFBP1 (WT UFBP1) but not by a mutant form of UFBP1 lacking the main ufmylation site lys267 (UFBP1 K267R). In vivo, ufmylation on UFBP1 ameliorated obesity, hepatic steatosis, hepatic lipogenesis, dyslipidemia, insulin resistance and liver damage in mice with NAFLD induced by a high fat diet (HFD). We also demonstrated that the downregulation of UFBP1 induced ER stress, whereas the reintroduction or overexpression of UFBP1 alleviated ER stress in a manner dependent on ufmylation in NAFLD. This mechanism could be responsible for the amelioration of aberrant hepatic lipogenesis and insulin resistance in NAFLD. Our data reveal a protective role of ufmylation on UFBP1 against NAFLD and offer a specific target for NAFLD treatment.

Carya cathayensis Leaf Extract Exerts Estrogenic Effects on Hepatic Lipogenesis and Adipocytes Differentiation in Ovariectomized Rats Fed Normal or High-fat Diets

Our previous study has shown that total flavonoids from the leaves of C arya . cathayensis exert estrogenic activities by promoting the expressions of ERα, ERβ in vitro study. C. cathayensis leaf extract (CCE) was rich in flavonoids. Oral administration of CCE reduced the serum lipids and hepatic lipids, alleviated liver steatosis in ovariectomized rats. To investigate whether CCE has estrogenic effects on reproductive tissue and lipid metabolism in ovariectomized rats, and whether CCE has a direct effect on regulation of lipid synthesis and/or oxidation and adipocyte differentiation of ovariectomized (OVX) rats. Sprague–Dawley rats were ovariectomized and treated with CCE or estradiol in combination with a normal diet (ND), a high-fat diet (HFD) for 8 weeks. Histological analysis of uterus were performed and the lipid metabolism-related enzyme activity were examined. Expression of liver lipogenesis-related genes, adipocyte differentiation-and fat accumulation-related genes and protein were measured. Ovariectomy accelerated the uterine atrophy, development of dyslipidemia and hepatic steatosis, which were effectively mitigated by CCE supplementation. CCE significantly elevated ovariectomy-induced reduction in the cross-section area of the uterus and uterine glands. Compared with the OVX group, CCE increased the activities of lipoprtein lipase (LPL) and hepatic lipase (HL), decreased the hepatic mRNA expressions of Fas, Srebf1 , and Sla2a2 and increased Ppar α expressions at the mRNA levels under both ND and HFD conditions. CCE also decreased the Pck1 and G6pc mRNA expressions under HFD conditions, and show no significant effects on Hmgcr . The expressions of SREBP-1c, CEBPA and VEGF at the protein level were effectively regulated by CCE supplementation. CCE effectively alleviated ovariectomy-induced dyslipidemia and visceral fat accumulation by modulating hepatic lipogenesis and adipocyte differentiation. Furthermore, CCE exhibited estrogenic activity for the prevention of postmenopausal fatty liver.

Multiomics analyses reveal dose-dependent effects of dicofol exposure on host metabolic homeostasis and the gut microbiota in mice

BackgroundEnvironmental exposure to dicofol (DCF), one of common organochlorine pesticides (OCPs) widely used for controlling agricultural pests, elicits a potential risk for human health due to its toxicity. However, potential physiological hazards of oral DCF exposure remain largely unknown. MethodsMice were exposed to relatively chronic and subacute DCF at different doses (5, 20 and 100 mg/kg) by gavage for 2 weeks. 1H NMR-based metabolomics was used to explore alterations of metabolic profiling induced by DCF exposure. Targeted metabolomics was subsequently employed to investigate the dose-dependent effects of oral DCF exposure on lipid metabolism and the gut microbiota-derived metabolites of mice. 16S rRNA gene sequencing was further employed to evaluate the changes of gut community of mice exposed to DCF. ResultsOral exposure to DCF dose-dependently induced liver injury, manifested by hepatic lipogenesis, inflammation and liver dysfunction of mice. Typically, DCF exposure disrupted host fatty acids metabolism that were confirmed by marked alteration in the levels of related genes. DCF exposure also dose-dependently caused dysbiosis of the gut bacteria and its metabolites including altered microbial composition accompanied by inhibition of bacterial fermentation. ConclusionThese results provide metabolic evidence that DCF exposure dose-dependently induces liver lipidosis and disruption of the gut microbiota in mice, which enrich our views of molecular mechanism of DCF hepatoxicity.