Secreted Frizzled-Related Protein 5 Mediates Wnt5a Expression in Microcystin-Leucine-Arginine-Induced Liver Lipid Metabolism Disorder in Mice

Objective Microcystin-leucine-arginine(MC-LR)exposure induces lipid metabolism disorders in the liver.Secreted frizzled-related protein 5(SFRP5)is a natural antagonist of winglesstype MMTV integration site family,member 5A(Wnt5a)and an anti-inflammatory adipocytokine.In this study,we aimed to investigate whether MC-LR can induce lipid metabolism disorders in hepatocytes and whether SFRP5,which has anti-inflammatory effects,can alleviate the effects of hepatic lipid metabolism by inhibiting the Wnt5a/Jun N-terminal kinase(JNK)pathway.Methods We exposed mice to MC-LR in vivo to induce liver lipid metabolism disorders.Subsequently,mouse hepatocytes that overexpressed SFRP5 or did not express SFRP5 were exposed to MC-LR,and the effects of SFRP5 overexpression on inflammation and Wnt5a/JNK activation by MC-LR were observed.Results MC-LR exposure induced liver lipid metabolism disorders in mice and significantly decreased SFRP5 mRNA and protein levels in a concentration-dependent manner.SFRP5 overexpression in AML12cells suppressed MC-LR-induced inflammation.Overexpression of SFRP5 also inhibited Wnt5a and phosphorylation of JNK.Conclusion MC-LR can induce lipid metabolism disorders in mice,and SFRP5 can attenuate lipid metabolism disorders in the mouse liver by inhibiting Wnt5a/JNK signaling.

Dietary pattern and hepatic lipid metabolism

The liver is the leading site for lipid metabolism,involving not only fatty acid beta-oxidation but also de novo synthesis of endogenous triglycerides and ketogenesis.The liver maintains systemic lipid homeostasis by regulating lipid synthesis,catabolism,and transportation.Dysregulation of hepatic lipid metabolism precipitates disorders,such as non-alcoholic fatty liver disease(NAFLD),affecting the whole body.Thus,comprehending and studying hepatic lipid metabolism is crucial for preventing and treating metabolic liver diseases.Traditionally,researchers have investigated the impact of a single nutrient on hepatic lipid metabolism.However,real-life dietary patterns encompass diverse nutrients rather than single components.In recent years,there have been increased studies and notable progress regarding the effects of distinct dietary patterns on hepatic lipid metabolism.This review summarizes the influence of diverse dietary patterns on hepatic lipid metabolism,elucidating underlying molecular mechanisms and appraising the therapeutic potential of dietary patterns in managing hepatic steatosis.

Dietary glutamine,glutamate,and aspartate supplementation improves hepatic lipid metabolism in post-weaning piglets

A previous study has demonstrated that early weaning significantly suppressed hepatic glucose metabolism in piglets.Glutamate(Glu),aspartate(Asp)and glutamine(Gln)are major metabolic fuels for the small intestine and can alleviate weaning stress,and therefore might improve hepatic energy metabolism.The objective of this study was to investigate the effects of administration of Glu,Asp and Gln on the expression of hepatic genes and proteins involved in lipid metabolism in post-weaning piglets.Thirty-six weaned piglets were assigned to the following treatments:control diet(Control;basal diet+15.90 g/kg alanine);Asp,Gln and Glu-supplemented diet(Control+AA;basal diet+1.00 g/kg Asp+5.00 g/kg Glu+10.00 g/kg Gln);and the energy-restricted diet supplemented with Asp,Gln and Glu(Energy^-+AA;energy deficient diet+1.00 g/kg Asp+5.00 g/kg Glu+10.00 g/kg Gln),Liver samples were obtained on d 5 and 21 post-weaning.Piglets fed Energy^-+AA diet had higher liver mRNA abundances of acyl-CoA oxidase 1(ACOX1),succinate dehydrogenase(SDH),mitochondrial transcription factor A(TFAM)and sirtuin 1(SIRT1),as well as higher protein expression of serine/threonine protein kinase 11(LKB1),phosphor-acetyl-CoA carboxylase(P-ACC)and SIRT1 compared with piglets fed control diet(P<0.05)on d 5 post-weaning.Control+AA diet increased liver malic enzyme 1(ME1)and SIRT1 mRNA levels,as well as protein expression of LKBl and P-ACC on d 5 post-weaning(P<0.05).On d 21 post-weaning,compared to control group,Glu,Gln and Asp supplementation up-regulated the mRNA levels of ACOX1,ME1 and SIRT1(P<0.05).These findings indicated that dietary Glu,Gln and Asp supplementation could improve hepatic lipid metabolism to some extent,which may provide nutritional intervention for the insufficient energy intake after weaning in piglets.

Effects of Bacillus subtilis on hepatic lipid metabolism and oxidative shess response in grass carp(Ctenopharyngodon idellus)fed a high-fat diet

Bacillus subtilis is widely used in aquaculture as a probiotic.However,few studies have been conducted to examine the effect of B.subtilis on liver lipid metabolism.A total of 135 healthy grass carp(50.24±1.38 g)were randomly divided into three groups:control(Con),high-fat diet(HF),and high-fat diet+B.subtilis(HF4-B.subtilis),and fed for 8 weeks.The results showed that compared with the HF group,the weight gain rate(WGR)significantly increased(Pc0.05)and the hepatic lipid content,serum low-density lipoprotein cholesterol(LDL-C),and aspartate aminotransferase(AST)decreased in the group supplemented with B.subtilis(P<0.05).Moreover,the hepatic mRNA expression of fatty acid synthase(FAS)was significantly down-regulated and the carnitine palmitoyl transferases(CPTlala)were up-regulated in the HF+B.subtilis group compared to the HF group(P<0.05),respectively.Additionally,in the HF+B.subtilis group,glutathione(GSH)significantly increased(Pv 0.()5),while hydrogen peroxide(H2O2)and malondialdehyde(MDA)contents significantly decreased compared to the HF group(P v0.05).B.subtilis may reduce the hepatic lipid content by inhibiting its synthesis and promoting p-oxidation of fatty acids.B.subtilis may also alleviate dyslipidaemia and prevent oxidative damage in the liver caused by the high-fat diet of grass carp.Hence,dietary supplementation with B.subtilis shows promise as a therapeutic or preventive tool against fatty liver disease.

The Action of p-Synephrine on Lipid Metabolism in the Perfused Rat Liver

p-synephrine and p-octopamine were found to increase lipolysis in adipocytes. The present study approaches the question if these compounds, natural products of the bitter orange (Citrus aurantium fruit), increase lipolysis and fatty acid oxidation in the liver. Experiments were done in the perfused rat liver. Non-recirculating hemoglobin-free perfusion was done using the Krebs/ Henseleit-bicarbonate buffer (pH 7.4) as perfusion fluid. Both p-synephrine and p-octopamine, at the concentrations of 100 μM, were found to stimulate the hepatic triacylglycerol lipase by 40% and 51%, respectively. These seem to be the maximal stimulations possible in the liver. In the perfused liver, p-synephrine, when present at an initial concentration of 500 μM, was able to increase the non-esterified fatty acid release after one hour of recirculating perfusion. The effects of p-synephrine on the oxidation of exogenously supplied [1-14C]octanoate and [1-14C]oleate were minimal. Only oxygen uptake, already stimulated by octanoate or oleate, was additionally increased by the infusion of p-synephrine. These results contrast with those obtained in a previous study with p-octopamine, which increased the production of 14CO2 from both [1-14C]octanoate and [1-14C]oleate. Apparently only the oxidation of endogenous fatty acids is stimulated by p-synephrine. On the other hand, both p-synephrine and p-octopamine stimulate the hepatic triacylglycerol lipase to a much lesser extent than the adipocyte lipase. It can be concluded that p-synephrine affects much more carbohydrate metabolism in the liver than lipid metabolism.

Changes in lipid metabolism in chronic hepatitis C

AIM: To investigate the relationship between certain biochemical parameters of lipid metabolism in the serum and steatosis in the liver.METHODS: The grade of steatosis (0-3) and histological activity index (HAI, 0-18) in liver biopsy specimens were correlated with serum alanine aminotransferase (ALT), total cholesterol and triglyceride levels in 142 patients with chronic hepatitis C (CH-C), and 28 patients with non-alcoholic fatty liver disease (NAFLD) without hepatitis C virus (HCV) infection. The serum parameters were further correlated with 1 797 age and sex matched control patients without any liver diseases.RESULTS: Steatosis was detected in 90 out of 142 specimens (63%) with CH-C. The ALT levels correlated with the grade of steatosis, both in patients with CH-C and NAFLD (P＜0.01). Inserting the score values of steatosis as part of the HAI, correlation with the ALT level (P＜0.00001) was found. The triglyceride and cholesterol levels were significantly lower in patients with CH-C (with and without steatosis), compared to the NAFLD group and to the virus-free control groups.CONCLUSION: Our study confirms the importance of liver steatosis in CH-C which correlates with lower lipid levels in the sera. Inclusion of the score of steatosis into HAI, in case of CH-C might reflect the alterations in the liver tissue more precisely, while correlating with the ALT enzyme elevation.

Inhibitory effect of schisandrin B on free fatty acid-induced steatosis in L-02 cells

AIM:To investigate the effects of schisandrin B (Sch B) on free fatty acid (FFA)-induced steatosis in L-02 cells.METHODS:Cellular steatosis was induced by incubating L-02 cells with a FFA mixture (oleate and palmitate at the ratio of 2:1) for 24 h.Cytotoxicity and apoptosis were evaluated by 3-(4,5-dmethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and Annexin V/propidium iodide staining,respectively.Cellular total lipid was determined using a photocolorimetric method after Nile red staining,and triglyceride content was measured using an enzymatic kit.To study the effects of Sch B on steatosis,L-02 cells were treated with Sch B (1-100 μmol/L) in the absence or presence of 1 mmol/L FFA for 24 h,and cellular total lipid and triglyceride levels were measured.To explore the mechanisms of action of Sch B in the steatotic L-02 cells,mRNA levels of several regulators of hepatic lipid metabolism including adipose differentiation related protein (ADRP),sterol regulatory element binding protein 1 (SREBP-1),peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ were measured by quantitative real-time polymerase chain reaction (PCR),and protein levels of ADRP and SREBP-1 were measured by immunoblotting.RESULTS:Treatment with 1 mmol/L FFA for 24 h induced intracellular lipid accumulation in L-02 cells comparable to that in human steatotic livers without causing apparent apoptosis and cytotoxicity.Sch B mitigated cellular total lipid and triglyceride accumulations in the steatotic L-02 cells in a dose-dependent manner.Quantitative real-time PCR and Western blot analyses revealed that treatment of L-02 cells with 100 μmol/L Sch B reverted the FFA-stimulated up-regulation of ADRP and SREBP-1.CONCLUSION:Sch B inhibits FFA-induced steatosis in L-02 cells by,at least in part,reversing the up-regulation of ADRP and SREBP-1.

Entry of hepatitis C virus into the cell: A therapeutic target

Several receptors have been identified as implicated on viral entry into the hepatocyte; and, this interaction between the virus and potential receptors could modulate infection, spontaneous viral clearance, persistence of the infection and the widespread of the virus as outbreak. Nevertheless, the playing role of each of them remains controversial. The NiemannPick type C1 like 1 gene (NPC1L1) receptor has been recently implicated on hepatitis C virus (HCV) entry into the cell and ezetimibe, an anti-cholesterol drug seems to block that, emerging the idea to control hepatitis C outbreak modulating lipid-related receptors. Hepatitis C infection seems to modulate lipid metabolism according to host genetic background. Indeed, it circulates like a lipoviroparticle. The main aim of this field of vision would be to discuss the role of hepatocyte receptors implicated on virus entry, especially NPC1L1 and the therapeutic options derived from the better knowledge about HCV-lipidsreceptors interaction.

Interaction between stress responses and circadian metabolism in metabolic disease

Circadian rhythms play crucial roles in orchestrating diverse physiological processes that are critical for health and disease.Dysregulated circadian rhythms are closely associated with various human metabolic diseases,including type 2 diabetes,cardiovascular disease,and non-alcoholic fatty liver disease.Modern lifestyles are frequently associated with an irregular circadian rhythm,which poses a significant risk to public health.While the central clock has a set periodicity,circadian oscillators in peripheral organs,particularly in the liver,can be entrained by metabolic alterations or stress cues.At the molecular level,the signal transduction pathways that mediate stress responses interact with the key determinants of circadian oscillation to maintain metabolic homeostasis under physiological or pathological conditions.In the liver,a number of nuclear receptors or transcriptional regulators,which are regulated by metabolites,hormones,the circadian clock,or environmental stressors,serve as direct links between stress responses and circadian metabolism.In this review,we summarize recent advances in the understanding of the interactions between stress responses(endoplasmic reticulum stress response,oxidative stress response,and inflammatory responses)and circadian metabolism,and the role of these interactions in the development of metabolic diseases.

New insight into inter-organ crosstalk contributing to the pathogenesis of non- alcoholic fatty liver disease （NAFLD）

Non-alcoholic fatty liver disease （NAFLD） is the most common cause of chronic liver dysfunction and a sig- nificant global health problem with substantial rise in prevalence over the last decades. It is becoming increasingly clear that NALFD is not only predominantly a hepatic manifestation of metabolic syndrome, but also involves extra-hepatic organs and regulatory pathways. Therapeutic options are limited for the treatment of NAFLD. Accordingly, a better understanding of the pathogenesis of NAFLD is critical for gaining new insight into the regulatory network of NAFLD and for identifying new targets for the prevention and treatment of NAFLD. In this review, we emphasize on the current understanding of the inter-organ crosstalk between the liver and peripheral organs that contributing to the pathogenesis of NAFLD.