Androgen signaling inhibits de novo lipogenesis to alleviate lipid deposition in zebrafish

Testosterone is closely associated with lipid metabolism and known to affect body fat composition and muscle mass in males.However,the mechanisms by which testosterone acts on lipid metabolism are not yet fully understood,especially in teleosts.In this study,cyp17a1-/-zebrafish(Danio rerio)exhibited excessive visceral adipose tissue(VAT),lipid content,and up-regulated expression and activity of hepatic de novo lipogenesis(DNL)enzymes.The assay for transposase accessible chromatinwithsequencing(ATAC-seq)results demonstrated that chromatin accessibility of DNL genes was increased in cyp17a1-/-fish compared to cyp17a1+/+male fish,including stearoyl-CoA desaturase(scd)and fatty acid synthase(fasn).Androgen response element(ARE)motifs in the androgen signaling pathway were significantly enriched in cyp17a1+/+male fish but not in cyp17a1-/-fish.Both androgen receptor(ar)-/-and wildtype(WT)zebrafish administered with Ar antagonist flutamide displayed excessive visceral adipose tissue,lipid content,and up-regulated expression and activity of hepatic de novo lipogenesis enzymes.The Ar agonist BMS-564929 reduced the content of VAT and lipid content,and down-regulated acetyl-CoA carboxylase a(acaca),fasn,and scd expression.Mechanistically,the rescue effect of testosterone on cyp17a1-/-fish in terms of phenotypes was abolished when ar was additionally depleted.Collectively,these findings reveal that testosterone inhibits lipid deposition by down-regulating DNL genes via Ar in zebrafish,thus expanding our understanding of the relationship between testosterone and lipid metabolism in teleosts.

Metabolic complications of psychotropic medications in psychiatric disorders:Emerging role of de novo lipogenesis and therapeutic consideration

Although significant advances have been made in understanding the pathophysiology of psychiatric disorders(PDs),therapeutic advances have not been very convincing.While psychotropic medications can reduce classical symptoms in patients with PDs,their long-term use has been reported to induce or exaggerate various pre-existing metabolic abnormalities including diabetes,obesity and non-alcoholic fatty liver disease(NAFLD).The mechanism(s)underlying these metabolic abnormalities is not clear;however,lipid/fatty acid accumulation due to enhanced de novo lipogenesis(DNL)has been shown to reduce membrane fluidity,increase oxidative stress and inflammation leading to the development of the aforementioned metabolic abnormalities.Intriguingly,emerging evidence suggest that DNL dysregulation and fatty acid accumulation could be the major mechanisms associated with the development of obesity,diabetes and NAFLD after long-term treatment with psychotropic medications in patients with PDs.In support of this,several adjunctive drugs comprising of anti-oxidants and antiinflammatory agents,that are used in treating PDs in combination with psychotropic medications,have been shown to reduce insulin resistance and development of NAFLD.In conclusion,the above evidence suggests that DNL could be a potential pathological factor associated with various metabolic abnormalities,and a new avenue for translational research and therapeutic drug designing in PDs.

Effect of dietary docosahexaenoic acid on lipogenesis and lipolysis in black sea bream,Acanthopagrus schlegeli

Hatchery-roared juvenile black sea breams are characterized by a low level of highly unsaturated fatty acids in their bodies, as compared with wild fish. To assess the effect of docosahaxaenoic acid （DHA） on lipegenic and lipelysis enzymes, one-year fish were roared on a casein-based purified diet and a DHA fortified diet （ 1.5% DHA ethyl ester/kg diet） for 60 d, followed with a period of 55 d for starvation. Dietary DHA was effectively incorporated into the fish body. Fortification of DHA depressed activities of glucose-6-phosphate dehydrogenase and NADP-isocitrate dehydrogenase as lipogenic enzymes in the hepatopancroas and intraperitoneal fat body. Carnitine palmitoyltransferase as lipolysis enzyme in the hepatopancreas was active in the DHA fortified fish. Starvation after feeding experiment induced increased carnitine palmitoyltransferase activity in both control and DHA fortified fish and the activity remained higher in the DHA fortified fish, while the monoenes were selectively consumed prior to highly unsaturated fatty acids. These results indicated that dietary DHA depressed lipogenesis and activated lipolysis.

Hepatic Lipogenesis Associated with Biochemical Changes in Overfed Landaise Geese and China Xupu Geese

This experiment studied hepatic lipogenesis associated with biochemical changes in overfed Landaise Geese and China Xupu geese. Twenty healthy male Landaise geese and 20 healthy male Xupu geese, hatched on the same day under the same feeding conditions, were selected as experimental animals. The animals were divided into two groups and each breed served as an experimental group. Per goose of per experimental group served for a repeat. Brown rice was selected as test diet. After overfeeding for 21 d and then slaughtering, the biochemical changes of hepatic lipogenesis in the genetic susceptibility to fatty liver were evaluated. These results showed that （1） the weight of fatty liver of the two breeds of geese were 801 and 375 g （P〈0.05）, respectively. There were no differences on the abdominal fat pat, filet total and filet pectoralis major in the two breeds experimental of the geese group （P〈0.05） and no difference on body and filet skin plus subcutaneous adipose tissue （P〉0.05） was found; （2） in these two breeds of geese, there were no differences on very-lowdensity lipoprotein （VLDL）, cholesteryl esters （CE） （P〈0.05）, free cholesterol （FC）, triglycerides （TG）, phospholipids （PL） and protein （P 〈 0.05）; （3） there were no differences on activities of malic enzyme （ME）, glucose-6-phosphatedehydrogenase （G6PDH）, acetyl-CoA-carboxylas （ACX）, fatty acid synthase （FAS）, and mRNA level of ME in the two experimental breeds of geese groups （P 〈0.05）; （4） test in Landaise geese group showed that there was no significant correlation with the specific enzymatic activities, while in Xupu geese group, the liver weight was negatively correlated to the specific activity of ACX and positively to that of ME; （5） in these overfed geese, ME activity appeared to be a major factor involved in the genetic susceptibility to hepatic steatosis and it determined the hepatic lipogenesis capacity.

Three Important Transcription Factors Related to Lipogenesis and Adipogenesis in Mammal

Lipid metabolism and adipocyte differentiation are reglulated by networking of transcription factors. It is generally known that three factors, peroxisome proliferator-activated receptor y （PPARγ）, CCAAT/element-binding protein a （C/EBPa） and sterol regulatory element binding protein-1 （SREBP1）, play fundamental roles in metabolic pathways. And they are also important in adipocyte differentiation. Expressions of these factors are regulated by some compounds such as fatty acids or some steroid hormones （insulin） which is stimulated by the nutritional level. Furthermore, these factors are related to some metabolic diseases including type II diabetes and obesity, Lots of researches have focused on relationships between the factors and the genetic diseases. Different functions of factors on inducing the adipocyte differentiation are other hot spots according to previous studies. This paper summarized these studies and gave a limpid description of structures and functions of these genes.

Role of unfolded protein response in lipogenesis

The signal transduction network in regulating lipid metabolism is a hot topic of biomedical research. Recent research endeavors reveal that intracellular stress signaling from a cellular organelle called endoplasmic reticulum (ER) is critically involved in lipid homeostasis and the development of metabolic disease. The ER is a site where newly-synthesized proteins are folded and assembled into their three-dimensional structures, modified and transported to their precise cellular destinations. A wide range of biochemical, physiological and pathological stimuli can interrupt the protein folding process in the ER and cause accumulation of unfolded or misfolded proteins in the ER lumen, a condition referred to as ER stress. To cope with this stress condition, the ER has evolved highly-specifi c signaling pathways collectively termed Unfolded Protein Response (UPR) or ER stress response. The UPR regulates transcriptionaland translational programs, affecting broad aspects of cellular metabolism and cell fate. Lipogenesis, the metabolic process of de novo lipid biosynthesis, occurs primarily in the liver where metabolic signals regulate expression of key enzymes in glycolytic and lipogenic pathways. Recent studies suggest that the UPR plays crucial roles in modulating lipogenesis under metabolic conditions. Here we address some of recent representative evidence regarding the role of the UPR in lipogenesis.

Pterostilbene induces cell apoptosis and inhibits lipogenesis in SKOV3 ovarian cancer cells by activation of AMPK-induced inhibition of Akt/mTOR signaling cascade

This study investigates if the anti-tumor effect of Pterostilbene in the SKOV3 ovarian cancer(OC)cell line involves inhibition of cell metabolism and tested in this effect involves modulating AMPK and Akt-induced regulation of mTORC1.Initially,SKOV3 cells were cultured in the humidified conditions in DMEM media for 24 h with or without increasing concentration of Pterostilbene.Then,the cells were incubated with Pterostilbene(IC_(50)=50μM)under similar conditions with or without pre-incubation with Dorsomorphin,an AMPK inhibitor.In a dose-dependent manner,Pterostilbene inhibited SKOV3 cell survival and increased their lysate levels of lactate dehydrogenase(LDH)and single-stranded DNA(ssDNA).When SKOV3 cells were treated with 50μM Pterostilbene,Pterostilbene significantly suppressed cell migration and invasion,reduced lysate levels of lactic acid and the optical density of Oil Red O staining,and increased lysate glucose levels.It also increased levels of malondialdehyde(MDA),reactive oxygen species(ROS),and induced intrinsic cell apoptosis by upregulating protein levels of Bax and cleaved caspase-3 and reducing protein levels of Bcl-2.Besides,Pterostilbene reduced mRNA levels of sterol regulatory element-binding protein 1(SREBP-1),fatty acid synthase(FAS),acetyl CoA carboxylase-1(ACC-1),and AMP-activated protein kinase(AMPK).Furthermore,Pterostilbene increased the protein levels of p-AMPK,p-p53,p-raptor,p-TSC-2,but significantly decreased protein levels of p-Akt,p-TSC-2,p-mTOR,p-S6K1,and p-4E-BP.Treatment with Dorsomorphin(CC)abolished all the anti-tumorigenesis effects afforded by Pterostilbene and prevented Pterostilbene-induced phosphorylation of Akt,p53,and mTOR.In conclusion,the tumorsuppressive effect of Pterostilbene in SKOV3 cells involves the induction of ROS and inhibition of dysregulation cell metabolism mainly due to AMPK-induced Akt-dependent or independent suppression of mTOR.

Cyanidine-3-O-Galactoside Enriched <i>Aronia melanocarpa</i>Extract Inhibits Adipogenesis and Lipogenesis via Down-Regulation of Adipogenic Transcription Factors and Their Target Genes in 3T3-L1 Cells

Aronia melamocarpa (AM) is a rich source of anthocyanins, which are known to help prevent obesity. The cyanidine-3-O-galactoside enriched AM extract (AM-Ex) containing more cyanidine-3-O-galactoside than conventional AM extract was recently developed. The objective of this study was to examine the effect of AM-Ex on adipogenesis and its action mechanisms in vitro using 3T3-L1 adipocytes. To examine the anti-obesity effect of AM-Ex, 3T3-L1 cells were induced adipocyte differentiation and incubated with various concentration of AM-Ex. Lipid accumulation, cellular triglyceride content, mRNA expression of transcription factors and adipogenic genes were analyzed. Treatment with 100 - 400 μg/mL of AM-Ex resulted in a dose-dependent decrease in adipocyte differentiation and triglyceride accumulation. mRNA expression of adipogenic transcription factors, such as peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein α, sterol regulatory element-binding protein 1 were decreased. The level of gene expression of adipogenesis and lipogenesis-related genes, such as adipocyte protein 2, lipoprotein lipase, acetyl-CoA carboxylase, ATP-citrate lyase and fatty acid synthase were decreased. These results suggest that AM-Ex alleviated risk factors related to obesity by modulating multiple pathways associated with adipogenesis.

Propofol suppressed cell proliferation through inhibition ofSREBP1c-mediated De novo lipogenesis in colorectal cancer cells

Background: De novo lipogenesis (DNL) is a critical event for the development of tumors, in the present work,we revealed the role of propofol in colorectal cancer (CRC) cell proliferation. Methods: Western blotting (WB), Real-timePCR, and luciferase combined with chromatin immunoprecipitation (ChIP) were used to identify the mechanismunderlying propofol-modulated cell proliferation in CRC cells. Results: Herein, we showed that propofol suppressedcell proliferation, which was attributed to the inhibition of DNL characterized by reduced fatty acid synthase (FASN),acetyl-coA carboxylase alpha (ACCA), and stearoyl-coA desaturase-1 (SCD1) expression. Mechanically, propofolstimulation decreased sterol regulatory element-binding proteins-1c (SREBP-1c) mature and nuclear translocation,which further decreased SCD1 transactivation confirmed by luciferase and ChIP analysis, while no significantdifference in total SREBP1c was observed. What’s more, supplementation of Monounsaturated fatty acid (MuFA)could reverse the inhibitory effect of propofol on cell proliferation. Conclusion: Taken together, these resultssuggested propofol modulated cell proliferation is dependent on SREBP1c-mediated DNL.

Suppressing Wnt signaling of the blood-tumor barrier to intensify drug delivery and inhibit lipogenesis of brain metastases

Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments.Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood-tumor barrier(BTB).BTB activates its Wnt signaling to maintain barrier properties,e.g.,Mfsd2a-mediated BTB low transcytosis.Here,we reported VCAM-1-targeting nano-wogonin(W@V-NPs)as an adjuvant of nano-orlistat(O@V-NPs)to intensify drug delivery and inhibit lipogenesis of brain metastases.W@V-NPs were proven to be able to inactivate BTB Wnt signaling,downregulate BTB Mfsd2a,accelerate BTB vesicular transport,and enhance tumor accumulation of O@V-NPs.With the ability to specifically kill cancer cells in a lipid-deprived environment with IC_(50) at 48 ng/mL,W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model mice.The combination did not induce brain edema,cognitive impairment,and systemic toxicity in healthy mice.Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.

Role of X-Box Binding Protein-1 in Fructose-Induced De Novo Lipogenesis in HepG2 Cells

Background：A high consumption of fructose leads to hepatic steatosis.About 20-30% of triglycerides are synthesized via de novo lipogenesis.Some studies showed that endoplasmic reticulum stress （ERS） is involved in this process,while others showed that a lipotoxic environment directly influences ER homeostasis.Here,our aim was to investigate the causal relationship between ERS and fatty acid synthesis and the effect of X-box binding protein-1 （XBP-1）,one marker of ERS,on hepatic lipid accumulation stimulated by high fructose.Methods：HepG2 cells were incubated with different concentrations of fructose.Upstream regulators of de novo lipogenesis （i.e.,carbohydrate response element-binding protein [ChREBP] and sterol regulatory element-binding protein 1 c [SREBP-lc]） were measured by polymerase chain reaction and key lipogenic enzymes （acetyl-CoA carboxylase [ACC],fatty acid synthase [FAS],and stearoyl-CoA desaturase-1 [SCD-1]） by Western blotting.The same lipogenesis-associated factors were then evaluated after exposure of HepG2 cells to high fructose followed by the ERS inhibitor tauroursodeoxycholic acid （TUDCA） or the ERS inducer thapsigargin.Finally,the same lipogenesis-associated factors were evaluated in HepG2 cells after XBP-1 upregulation or downregulation through cell transfection.Results：Exposure to high fructose increased triglyceride levels in a dose-and time-dependent manner and significantly increased mRNA levels of SREBP-1c and ChREBP and protein levels ofFAS,ACC,and SCD-1,concomitant with XBP-1 conversion to an active spliced form.Lipogenesis-associated factors induced by high fructose were inhibited by TUDCA and induced by thapsigargin.Triglyceride level in XBP-l-deficient group decreased significantly compared with high-fructose group （4.41 ± 0.54 μmol/g vs.6.52 ± 0.38 μmol/g,P 〈 0.001）,as mRNA expressions of SREBP-1c （2.92 ± 0.46 vs.5.08 ± 0.41,P 〈 0.01） and protein levels of FAS （0.53 ± 0.06 vs.0.85 ± 0.05,P =0.01）,SCD-1 （0.65 ± 0.06 vs.0.90 ± 0.04,P =0.04）,and ACC （0.38 ± 0.03 vs.0.95 ± 0.06,P 〈 0.01） decreased.Conversely,levels of triglyceride （4.22 ± 0.54 μmol/g vs.2.41 ± 0.35 μmol/g,P 〈 0.001）,mRNA expression of SREBP-1c （2.70 ± 0.33 vs.1.00 ± 0.00,P 〈 0.0 1）,and protein expression of SCD-1 （0.93 ± 0.06 vs.0.26 ± 0.05,P 〈 0.01）,ACC （0.98 ± 0.09 vs.0.43 ± 0.03,P 〈 0.01）,and FAS （0.90 ± 0.33 vs.0.71 ±4 0.02,P =0.04） in XBP-ls-upregulated group increased compared with the untransfected group.Conclusions：ERS is associated with de novo lipogenesis,and XBP-1 partially mediates high-fructose-induced lipid accumulation in HepG2 cells through augmentation of de novo lipogenesis.

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

Background:Our previous in vitro study has shown that total flavonoids from the leaves of Carya cathayensis exert estrogenic activities by promoting the expressions of ER𝛼and ER𝛽.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.Objective:To investigate whether CCE has estrogenic effects on reproductive tissue and influences 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.Methods:Female 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.Rusults: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,Sla2a2,and increased Ppar𝛼expressions 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 SREBF1,CEBPA and VEGF at the protein level were effectively regulated by CCE supplementation.Conclusion:CCE effectively alleviated ovariectomy-induced dyslipidemia and visceral fat accumulation by mod-ulating hepatic lipogenesis and adipocyte differentiation.Furthermore,CCE exhibited estrogenic activity for the prevention of postmenopausal fatty liver.

LIPOGENESIS STIMULATORY AND INHIBITORY ACTIVITIES OF THE INSULIN MEDIATORS

Incubating plasma membranes prepared from pig liver with varying concentrations of insulin (50—1000 μU/ml) resulted in the release of at least two insulin chemical mediators. One of them was fraction 1 of insulin mediator (M. W. 3700—4000 daltons) which had a significant lipogenesis-stimulatlug activity. The other was fraction 2 of insulin mediator (M. W. about 1000 daltons) which exhibited a lipogenesis-inhibitory activity.The ratio of yield between the two mediators produced from the membranes was not only dependent on the concentration but also on the potency of insulin and its analogs added. The result showed that there was more production of fraction 2 than fraction 1 with the inducer at low concentration (100 μU/ml), while the production of fraction 1 from the plasma membranes incubated with high concentration of insulin (300 μU/ml) was higher than fraction 2. On the other hand, insulin and its analogs which have different biological activities and receptor bindtng activities have been used to induce the insulin mediators. The results obtained were similar to those mentioned above. This suggested that the generation of the mediators was dependent on the biological potences but not the binding activities.

In-depth analysis of de novo lipogenesis in non-alcoholic fatty liver disease:Mechanism and pharmacological interventions

Non-alcoholic fatty liver disease(NAFLD)is characterized by the abnormal buildup of lipids in the liver tissue.Non-alcoholic fatty liver(NAFL)may progress to non-alcoholic steatohepatitis.Triglycerides in the liver can originate from various sources,including de novo lipogenesis(DNL).Research indicates that DNL significantly escalates in NAFLD,worsening steatosis.However,the precise regulatory mechanism of DNL in the development of this disease is not fully understood.Therefore,the targeted reduction of DNL could be a crucial therapeutic strategy.Currently,numerous pharmaceutical agents targeting DNL have been developed,attracting significant attention.This review examines the mechanism of DNL upregulation in NAFLD,assessing its potential as a therapeutic target for hepatic steatosis.Furthermore,we thoroughly examine hepatocellular lipotoxicity and provide an extensive review of the application and limitations of relevant therapeutic drugs,with a focus on key enzymes involved in DNL.The implementation of these pharmacological strategies is expected to significantly improve the management and overall outcomes for patients with NAFLD.

Carboxyl Ester Lipase Protects Against Metabolic Dysfunction-Associated Steatohepatitis by Binding to Fatty Acid Synthase

Carboxyl ester lipase(CEL),a pivotal enzyme involved in lipid metabolism,is recurrently mutated in obese mice.Here,we aimed to elucidate the functional significance,molecular mechanism,and therapeutic potential of CEL in metabolic dysfunction-associated steatohepatitis(MASH).Hepatocyte-specific carboxyl ester lipase gene(Cel)knockout(Cel^(DHEP))and wildtype(WT)littermates were fed with cholinedeficient high-fat diet(CD-HFD)for 16 weeks,or methionine-and choline-deficient diet(MCD)for three weeks to induce MASH.Liquid chromatography–mass spectrometry and co-immunoprecipitation were employed to identify the downstream targets of CEL.CD-HFD/MCD-fed WT mice received intravenous injections of CEL-adeno-associated viral,serotype 8(AAV8)to induce specific overexpression of CEL in the liver.We observed a decrease in CEL protein levels in MASH induced by CD-HFD or MCD in mice.Cel^(DHEP) mice fed with CD-HFD or MCD exhibited pronounced hepatic steatosis,inflammation,lipid peroxidation,and liver injury compared to WT littermates,accompanied by increased hepatic nuclear factor kappa-light-chain-enhancer of activated B cell(NF-jB)activation.Consistently,Cel knockdown in mouse primary hepatocytes and AML12 cells aggravated lipid accumulation and inflammation,whereas CEL overexpression exerted the opposite effect.Mechanistically,CEL directly bound to fatty acid synthase(FASN),resulting in reduced FASN SUMOylation,which in turn promoted FASN degradation through the proteasome pathway.Furthermore,inhibition of FASN ameliorated hepatocyte lipid accumulation and inflammation induced by Cel knockdown in vivo and in vitro.Hepatocyte-specific CEL overexpression using AAV8-Cel significantly mitigated steatohepatitis in mice fed with CD-HFD or MCD.CEL protects against steatohepatitis development by directly interacting with FASN and suppressing its expression for de novo lipogenesis.CEL overexpression confers a therapeutic benefit in steatohepatitis.

A novel bellidifolin intervention mitigates nonalcoholic fatty liver disease-like changes induced by bisphenol F

As a potential endocrine-disrupting chemical,bisphenol F(BPF)may cause nonalcoholic fatty liver disease(NAFLD)-like changes,but the mechanisms under its pathogenesis as well as the intervention strategies remain unclear.Using the electron microscopy technology,along with LipidTOX Deep Red neutral and Bodipy 493/503 staining assays,we observed that BPF treatment elicited a striking accumulation of lipid droplets in HepG2 cells,accompanied by an increased total level of triglycerides.At the molecular level,the lipogenesis-associated mRNAs and proteins,including acetyl-CoA carboxylase,fatty acid synthase,stearoyl-CoA desaturase-1,peroxisome proliferator-activated receptor gamma,and CCAAT-enhancer-binding proteins,increased significantly via the AMP-activated protein kinase(AMPK)-mammalian target of rapamycin(mTOR)signaling regulation in both in vitro and in vivo studies.Furthermore,the immunofluorescence results also showed the robust lipogenesis induced by BPF,evident in its ability to promote the translocation of sterol regulatory element-binding protein-1c from the cytoplasm to the nuclei.To investigate the intervention strategies for BPF-induced NAFLD-like changes,we demonstrated that bellidifolin,isolated and purified from Swertia chirayita,significantly attenuated BPF-induced lipid droplet deposition in HepG2 cells and NAFLD-like changes in mice by blocking the expression of lipogenesis-associated proteins.Therefore,the present study elucidates the mechanisms underlying the BPF-induced lipid accumulation in HepG2 cells,while also highlighting the potential of bellidifolin to mitigate BPF-induced NAFLD-like changes.

Fanlian Huazhuo Formula:A promising herbal preparation for metabolic liver disease

The prevalence of metabolic dysfunction-associated steatotic liver disease(MASLD)has increased significantly in recent decades and is projected to increase further due to the rising obesity rates.MASLD patients are at higher risk of developing advanced liver diseases“cirrhosis and hepatocellular carcinoma”as well as liver-or cardiovascular-related mortality.Existing lipid-lowering therapies failed to reduce the risk of mortality in these patients.Therefore,there is an urgent need for pharmacotherapies that can control and even reverse this disease.Fanlian Huazhuo Formula(FLHZF)is a combination herbal preparation,and its various individual constituents regulate hepatic lipid metabolism,adipose tissue inflammation,and gut microbiota.Despite,these useful effects,limited information is available on its benefits in diet-induced hepatosteatosis.In this article,we discuss the research findings recently published about the therapeutic effects of FLHZF in suppressing MASLD development and underlying mechanisms.Utilizing a series of in vitro and in vivo experiments,the authors demonstrated for the first time that FLHZF suppresses MASLD in male mice possibly by inhibiting hepatic de novo lipogenesis pathways and reducing hepatocyte death.This study paves the way for future investigations aimed at investigating FLHZF’s role in inhibiting lipogenesis particularly using radioactively-labeled glucose and acetate,and governing hepatocyte mitochondrial function,gut microbiome profile,and its effects in other models of MASLD,and female mice.

Antioxidant dietary approach in treatment of fatty liver: New insights and updates

Non-alcoholic fatty liver disease(NAFLD) is a common clinicopathological condition, encompassing a range of conditions caused by lipid deposition within liver cells. To date, no approved drugs are available for the treatment of NAFLD, despite the fact that it represents a serious and growing clinical problem in the Western world. Identification of the molecular mechanisms leading to NAFLD-related fat accumulation, mitochondrial dysfunction and oxidative balance impairment facilitates the development of specific interventions aimed at preventing the progression of hepatic steatosis. In this review, we focus our attention on the role of dysfunctions in mitochondrial bioenergetics in the pathogenesis of fatty liver. Major data from the literature about the mitochondrial targeting of some antioxidant molecules as a potential treatment for hepatic steatosis are described and critically analysed. There is ample evidence of the positive effects of several classes of antioxidants, such as polyphenols(i.e., resveratrol, quercetin, coumestrol, anthocyanins, epigallocatechin gallate and curcumin), carotenoids(i.e., lycopene, astaxanthin and fucoxanthin) and glucosinolates(i.e., glucoraphanin, sulforaphane, sinigrin and allyl-isothiocyanate), on the reversion of fatty liver. Although the mechanism of action is not yet fully elucidated, in some cases an indirect interaction with mitochondrial metabolism is expected. We believe that such knowledge will eventually translate into the development of novel therapeutic approaches for fatty liver.

Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease

Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease(NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors(PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation(mitochondrial and peroxisomal)and microsomal omega-oxidation, being markedly decreased by high-fat(HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs.

Green tea polyphenols ameliorate non-alcoholic fatty liver disease through upregulating AMPK activation in high fat fed Zucker fatty rats

AIM To investigate protective effects and molecular mechanisms of green tea polyphenols(GTP) on nonalcoholic fatty liver disease(NAFLD) in Zucker fatty(ZF) rats.METHODS Male ZF rats were fed a high-fat diet(HFD) for 2 wk then treated with GTP(200 mg/kg) or saline(5 m L/kg) for 8 wk, with Zucker lean rat as their control. At the end of experiment, serum and liver tissue were collected for measurement of metabolic parameters, alanine aminotransferase(ALT) and aspartate aminotransferase(AST), inflammatory cytokines and hepatic triglyceride and liver histology. Immunoblotting was used to detect phosphorylation of AMP-activated protein kinase(AMPK) acetyl-Co A carboxylase(ACC), and sterol regulatory element-binding protein 1c(SREBP1c). RESULTS Genetically obese ZF rats on a HFD presented with metabolic features of hepatic pathological changes comparable to human with NAFLD. GTP intervention decreased weight gain(10.1%, P = 0.052) and significantly lowered visceral fat(31.0%, P < 0.01). Compared with ZF-controls, GTP treatment significantly reduced fasting serum insulin, glucose and lipids levels. Reduction in serum ALT and AST levels(both P < 0.01) were observed in GTP-treated ZF rats. GTP treatment also attenuated the elevated TNFα and IL-6 in the circulation. The increased hepatic TG accumulation and cytoplasmic lipid droplet were attenuated by GTP treatment, associated with significantly increased expression of AMPK-Thr172(P < 0.05) and phosphorylated ACC and SREBP1c(both P < 0.05), indicating diminished hepatic lipogenesis and triglycerides out flux from liver in GTP treated rats. CONCLUSION The protective effects of GTP against HFD-induced NAFLD in genetically obese ZF rats are positively correlated to reduction in hepatic lipogenesis through upregulating the AMPK pathway.