Hepatic Lipid Levels Research Articles

Optimal dietary zinc inclusion improved growth performance, serum antioxidant capacity, immune status, and liver lipid and glucose metabolism of largemouth bass (Micropterus salmoides)

This study was conducted to ascertain the effect of dietary Zn on growth and health status of juvenile largemouth bass (Micropterus salmoides). Six experimental diets with Zn level of 50.17, 56.74, 73.34, 86.03, 123.94, and 209.20 mg/kg, respectively were compounded using complex amino acid-chelated zinc, and were fed to juvenile fish (5.50 ± 0.10 g) for 70 d. The specific growth rate (SGR) varied with dietary Zn level in a quadratic model and peaked at the 73.34 mg/kg group, while the feeding rate exhibited an opposite trend (P < 0.05). The condition factor, hepatosomatic index and mesenteric fat index all exhibited a tendency similar with SGR (P < 0.05). Dietary Zn level affected serum total proteins, urea, triglycerides, and glucose (P < 0.05). Serum Zn and copper levels linearly increased with dietary Zn level, while serum iron and manganese showed the opposite trend. Serum superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) increased with dietary Zn level and reached a plateau at 86.03 mg/kg. Serum complement component 3 (C3), IgM, and lysozyme also were enhanced by 73.34 mg/kg Zn. Body protein content increased with zinc level up to 73.34 mg/kg, and then remained steadily. As dietary Zn level increased, hepatic lipid level increased and then reached a plateau at 86.03 mg/kg group, while glycogen increased linearly. Moreover, gene expression related to lipid and glycogen metabolism from liver transcriptome further explained the liver lipid and glycogen variations. To conclude, a dietary Zn requirement of 76.99 mg/kg was suggested for juvenile largemouth bass to improve growth, antioxidant capacity, and immune status.

Interactive effects of cadmium and titanium dioxide nanoparticles on hepatic tissue in rats: Ameliorative role of coenzyme 10 via modulation of the NF-κB and TNFα pathway

This study investigated the effect of oral dosing of titanium dioxide nanoparticles (TNPs) and cadmium (Cd2+) on rat liver and the potential protective role of coenzyme Q10 (CQ10) against TNPs and Cd2+-induced hepatic injury. Seventy male Sprague Dawley rats were divided into seven groups and orally given distilled water, corn oil, CQ10 (10 mg/kg b.wt), TNPs (50 mg/kg b.wt), Cd2+ (5 mg/kg b.wt), TNPs + Cd2+, or TNPs + Cd2++CQ10 by gastric gavage for 60 successive days. The results showed that individual or mutual exposure to TNPs and Cd2+ significantly increased the serum levels of various hepatic enzymes and lipids, depleted the hepatic content of antioxidant enzymes, and increased malondialdehyde. Moreover, the hepatic titanium and Cd2+ content were increased considerably in TNPs and/or Cd2+-exposed rats. Furthermore, marked histopathological perturbations with increased immunoexpression of tumor necrosis factor-alpha and nuclear factor kappa B were evident in TNPs and/or Cd2+-exposed rats. However, CQ10 significantly counteracted the damaging effect of combined exposure of TNPs and Cd2+ on the liver. The study concluded that TNPs and Cd2+ exposure harm hepatic function and its architecture, particularly at their mutual exposure, but CQ10 could be a candidate protective agent against TNPs and Cd2+ hepatotoxic impacts.

Garcinia cambogia Extract Increased Hepatic Levels of Lipolysis-Stimulated Lipoprotein Receptor and Lipids in Mice on Normal Diet.

Garcinia cambogia extract (GCE) is a popular weight-loss supplement that also lowers plasma triglyceride (TG) levels. We hypothesized that GCE-mediated inhibition of ATP citrate lyase and thereby hepatic TG production could lead to compensatory mechanisms, including increased hepatic TG uptake via lipoprotein receptors. GCE (20 mg/day) administered 40 days orally to female C57BL/6Rj mice on a standard chow diet led to a decrease in both plasma fasting and post-prandial TG-rich lipoprotein levels, but with no significant change in body weight gain. Lipolysis stimulated lipoprotein receptor (LSR) protein levels, but not those of LDL-receptor, were increased as compared to controls. Mouse Hepa1-6 cells treated with the GCE active ingredient, hydroxycitrate, also led to increased LSR protein levels. Hepatic total cholesterol, TG, and muscle TG contents were higher in GCE-treated animals as compared to controls, whereas adipose TG levels were unchanged. LSR and LDL-receptor protein levels were correlated with liver total cholesterol, but only LDL-receptor was associated with liver TG. These results show that GCE treatment in mice on a standard chow diet led to significantly increased liver and muscle lipids, with no significant change in adipose tissue TG levels, which should be considered in the long-term use of GCE.

Effect of herbal extracts and Saroglitazar on high-fat diet-induced obesity, insulin resistance, dyslipidemia, and hepatic lipidome in C57BL/6J mice

We evaluated the effects of select herbal extracts (Tinospora cordifolia [TC], Tinospora cordifolia with Piper longum [TC + PL], Withania somnifera [WS], Glycyrrhiza glabra [GG], AYUSH–64 [AY-64], and Saroglitazar [S]) on various parameters in a diet-induced obesity mouse model. After 12 weeks of oral administration of the herbal extracts in high-fat diet (HFD)-fed C57BL/6J mice, we analyzed plasma biochemical parameters, insulin resistance (IR), liver histology, and the expression of inflammatory and fibrosis markers, along with hepatic lipidome. We also used a 3D hepatic spheroid model to assess their impact on profibrotic gene expression. Among the extracts, TC + PL showed a significant reduction in IR, liver weight, TNF-α, IL4, IL10 expression, and hepatic lipid levels (saturated triglycerides, ceramides, lysophosphocholines, acylcarnitines, diglycerides, and phosphatidylinositol levels). Saroglitazar reversed changes in body weight, IR, plasma triglycerides, glucose, insulin, and various hepatic lipid species (fatty acids, phospholipids, glycerophospholipids, sphingolipids, and triglycerides). With the exception of GG, Saroglitazar, and other extracts protected against palmitic acid-induced fibrosis marker gene expression in the 3D spheroids. TC + PL and Saroglitazar also effectively prevented HFD-induced insulin resistance, inflammation, and specific harmful lipid species in the liver.

Combined, elobixibat, and colestyramine reduced cholesterol toxicity in a mouse model of metabolic dysfunction-associated steatotic liver disease.

Cholesterol levels and bile acid metabolism are important drivers of metabolic dysfunction-associated steatohepatitis (MASH) progression. Using a mouse model, we investigated the mechanism by which cholesterol exacerbates MASH and the effect of colestyramine (a bile acid adsorption resin) and elobixibat (an apical sodium-dependent bile acid transporter inhibitor) concomitant administration on bile acid adsorption and MASH status. Mice were fed a high-fat high-fructose diet with varying concentrations of cholesterol to determine changes in fatty liver according to liver status, water intake, defecation status, insulin resistance, bile acid levels, intestinal permeability, atherosclerosis (in apolipoprotein E knockout mice), and carcinogenesis (in diethylnitrosamine mice). Using small interfering ribonucleic acid (siRNA), we evaluated the effect of sterol regulatory element binding protein 1c (SREBP1c) knockdown on triglyceride synthesis and fatty liver status following the administration of elobixibat (group E), colestyramine (group C), or both (group EC). We found greater reductions in serum alanine aminotransferase levels, serum lipid parameters, serum primary bile acid concentrations, hepatic lipid levels, and fibrosis area in EC group than in the monotherapy groups. Increased intestinal permeability and watery diarrhea caused by elobixibat were completely ameliorated in group EC. Group EC showed reduced plaque formation rates in the entire aorta and aortic valve of the atherosclerosis model, and reduced tumor counts and tumor burden in the carcinogenesis model. Excessive free cholesterol in the liver can promote fatty liver disease. Herein, combination therapy with EC effectively reduced free cholesterol levels in MASH model mice. Our study provides strong evidence for combination therapy as an effective treatment for MASH.

Sex-specific effects of acute chlordane exposure in the context of steatotic liver disease, energy metabolism and endocrine disruption.

Chlordane is an organochlorine pesticide (OCP) that is environmentally persistent. Although exposures to OCPs including chlordane have been associated with elevated liver enzymes, current knowledge on OCPs' contribution to toxicant-associated steatotic liver disease (TASLD) and underlying sex-specific metabolic/endocrine disruption are still widely limited. Therefore, the objective of this study was to investigate the sex-dependent effects of chlordane in the context of TASLD. Age-matched male and female C57BL/6 mice were exposed to chlordane (20mg/kg, one-time oral gavage) for two weeks. Female mice generally exhibited lower bodyfat content but more steatosis and hepatic lipid levels, consistent with increased hepatic mRNA levels of genes involved in lipid synthesis and uptake. Surprisingly, chlordane-exposed females demonstrated lower hepatic cholesterol levels. With regards to metabolic disruption, chlordane exposure decreased expression of genes involved in glycogen and glucose metabolism (Pklr, Gck), while chlordane-exposed females also exhibited decreased gene expression of HNF4A, an important regulator of liver identity and function. In terms of endocrine endpoints, chlordane augmented plasma testosterone levels in males. Furthermore, chlordane activated hepatic xenobiotic receptors, including the constitutive androstane receptor, in a sex-dependent manner. Overall, chlordane exposure led to altered hepatic energy metabolism, and potential chlordane-sex interactions regulated metabolic/endocrine disruption and receptor activation outcomes.

Rotundic acid alleviates hyperlipidemia in rats by regulating lipid metabolism and gut microbiota.

Disturbances in lipid metabolism and dysbiosis of the gut microbiota play an important role in the progression of hyperlipidemia. Previous study indicated that Ilicis Rotundae Cortex possesses anti-hyperlipidemic activity, and rotundic acid (RA) identified as a key active compound to be incorporated into the body. The study aimed to evaluate the anti-hyperlipidemia effects of RA and explored its impact on gut microbiota and lipid metabolism, as well as its possible mechanisms for improving hyperlipidemia. The study methodology included a comprehensive evaluation of the effects of RA on steatosis markers of hyperlipidemia, lipid metabolism, and gut microbiota by assessing biochemical parameters and histopathology, lipidomics, 16S rRNA gene sequencing, and short-chain fatty acid (SCFA) assays. The results showed that RA effectively reduced body weight and the steatosis markers in serum and liver. Moreover, the lipidomic analysis revealed significant changes in plasmatic and hepatic lipid levels, and these were restored by RA. According to the results of 16S rRNA gene sequencing, RA supplementation raised the relative abundance of Bacteroidetes and Proteobacteria while decreasing the relative abundance of Firmicutes. RA significantly boosted the relative abundance of SCFAs by increasing SCFAs-producing bacteria such as Bacteroides, Alloprevotella, Desulfovibrio, etc. In summary, RA could regulate triglyceride metabolism and glycerophospholipid metabolism, restore gut microbiota structure, and increase the relative abundance of SCFAs-producing bacteria to exert its hypolipidemic effects. These findings suggest RA to be a promising therapeutic agent for hyperlipidemia.

Integration of Transcriptomics and Lipidomics Profiling to Reveal the Therapeutic Mechanism Underlying Ramulus mori (Sangzhi) Alkaloids for the Treatment of Liver Lipid Metabolic Disturbance in High-Fat-Diet/Streptozotocin-Induced Diabetic Mice.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder, with a global prevalence of 25%. Currently, there remains no approved therapy. Ramulus mori (Sangzhi) alkaloids (SZ-As), a novel natural medicine, have achieved comprehensive benefits in the treatment of type 2 diabetes; however, few studies have focused on its role in ameliorating hepatic lipid metabolic disturbance. Herein, the therapeutic effect and mechanism of SZ-As on a high-fat diet (HFD) combined with streptozotocin (STZ)-induced NAFLD mice were investigated via incorporating transcriptomics and lipidomics. SZ-As reduced body weight and hepatic lipid levels, restored pathological alternation and converted the blood biochemistry perturbations. SZ-A treatment also remarkedly inhibited lipogenesis and enhanced lipolysis, fatty acid oxidation and thermogenesis. Transcriptomics analysis confirmed that SZ-As mainly altered fatty acid oxidative metabolism and the TNF signaling pathway. SZ-As were further demonstrated to downregulate inflammatory factors and effectively ameliorate hepatic inflammation. Lipidomics analysis also suggested that SZ-As affected differential lipids including triglyceride (TG) and phosphatidylcholine (PC) expression, and the main metabolic pathways included glycerophospholipid, sphingomyelins and choline metabolism. Collectively, combined with transcriptomics and metabolomics data, it is suggested that SZ-As exert their therapeutic effect on NAFLD possibly through regulating lipid metabolism pathways (glycerophospholipid metabolism and choline metabolism) and increasing levels of PC and lysophosphatidylcholine (LPC) metabolites. This study provides the basis for more widespread clinical applications of SZ-As.

Revealing the mechanism of Zanthoxylum armatum DC. extract-induced liver injury in mice based on lipidomics

Ethnopharmacological relevanceZanthoxylum armatum DC. (Z. armatum) is an herbal medicine with various active ingredients and pharmacological effects. However, modern studies found that Z. armatum is hepatotoxic. The liver is the target organ for toxic effects and an important site for lipid metabolism. The effects of Z. armatum on lipid level and metabolism in the liver are still unclear. Aim of the studyThis study aimed to analyze hepatic lipid levels, lipid metabolites and metabolic pathways of action of Z. armatum based on lipidomics, to investigate the potential hepatotoxic mechanism of Z. armatum. Materials and methodsDifferent doses (62, 96, and 150 mg/kg) of the methanolic extract of Z. armatum (MZADC) were administered to ICR mice by gavage. The hepatotoxicity of MZADC was assessed by the liver index, serum biochemical measurements, and histopathological examination. Lipid levels measured by the serum lipid index were evaluated in the mice. Lipidomics was used to screen for differential lipid metabolism markers and lipid metabolism pathways in the liver. Western blot analysis was performed to investigate the effects of MZADC on the liver. ResultsLiver index values and serum alanine transaminase and aspartate transaminase levels were increased in the MZADC group. Histopathology examination revealed hepatocyte necrosis, watery degeneration of the hepatocytes, and hepatic cord rupture in the livers of mice. Serum levels of low-density lipoprotein cholesterol, cholesterol, and triglycerides were elevated, and high-density lipoprotein cholesterol levels were decreased. Lipidomics screening for markers of differential lipid metabolism in the liver, and altered profiles of differential metabolites indicated that glycerophospholipid metabolism, linoleic acid metabolism, alpha-linolenic acid metabolism, glycosylphosphatidylinositol-anchored biosynthesis, sphingolipid metabolism and arachidonic acid metabolic pathways were significantly associated with MZADC-induced liver injury. Western blots confirmed that the protein expression of LC3, Beclin-1, ATG5, ATG12 and ATG16L1 was decreased, and p62 was increased in the MZADC group. The proportion of p-PI3K/PI3K and p-AKT/AKT was increased. ConclusionsThe liver injury induced by MZADC involved many different lipid metabolites and lipid metabolic pathways, which may be related to autophagy. This study provides a new perspective on the hepatotoxicity study of Z. armatum and provides a reference for the safe application of Z. armatum in the medicine and food fields.

Chronic-binge ethanol feeding aggravates systemic dyslipidemia in Ldlr-/- mice, thereby accelerating hepatic fibrosis.

Chronic ethanol consumption is known to cause alcohol-associated liver disease, which poses a global health concern as almost a quarter of heavy drinkers develop severe liver damage. Alcohol-induced liver disease ranges from a mild, reversible steatotic liver to alcoholic steatohepatitis and irreversible liver fibrosis and cirrhosis, ultimately requiring liver transplantation. While ethanol consumption is associated with dysregulated lipid metabolism and altered cholesterol homeostasis, the impact of dyslipidemia and pre-existing hypercholesterolemia on the development of alcohol-associated liver disease remains to be elucidated. To address the influence of systemic dyslipidemia on ethanol-induced liver disease, chronic-binge ethanol feeding was applied to female C57BL/6J (wild type) mice and mice deficient for the low-density lipoprotein receptor (Ldlr-/-), which display a human-like lipoprotein profile with elevated cholesterol and triglyceride levels in circulation. Respective control groups were pair-fed an isocaloric diet. Chronic-binge ethanol feeding did not alter systemic lipid levels in wild type mice. While increased systemic cholesterol levels in Ldlr-/- mice were not affected by ethanol feeding, chronic-binge ethanol diet aggravated elevated plasma triglyceride levels in Ldlr-/- mice. Despite higher circulatory triglyceride levels in Ldlr-/- mice, hepatic lipid levels and the development of hepatic steatosis were not different from wild type mice after ethanol diet, while hepatic expression of genes related to lipid metabolism (Lpl) and transport (Cd36) showed minor changes. Immunohistochemical assessment indicated a lower induction of infiltrating neutrophils in the livers of ethanol-fed Ldlr-/- mice compared to wild type mice. In line, hepatic mRNA levels of the pro-inflammatory genes Ly6g, Cd11b, Ccr2, Cxcl1 and F4/80 were reduced, indicating less inflammation in the livers of Ldlr-/- mice which was associated with reduced Tlr9 induction. While systemic ALT and hepatic MDA levels were not different, Ldlr-deficient mice showed accelerated liver fibrosis development after chronic-binge ethanol diet than wild type mice, as indicated by increased levels of Sirius Red staining and higher expression of pro-fibrotic genes Tgfb, Col1a1 and Col3a1. Ldlr-/- and wild type mice had similar plasma ethanol levels and did not show differences in the hepatic mRNA levels of Adh1 and Cyp2e1, important for ethanol metabolism. Our results highlight that chronic-binge ethanol feeding enhances systemic dyslipidemia in Ldlr-/- mice which might accelerate the development of hepatic fibrosis, independent of hepatic lipid levels.

Saudi date cultivars' seed extracts inhibit developing hepatic steatosis in rats fed a high-fat diet

This research aim was to assess the impact of the seed extracts of the date cultivars (Qatara, Barhi, and Ruthana) on rat’s liver steatosis, oxidative stress, and inflammation triggered by feeding a high-fat diet (HFD). The experimental design was based on random partitioning into two groups; one that received the standard diet and another that received the HFD diet. The HFD rats were orally administered Lipitor or date seed extracts at 300 or 600 mg/kg/day for 4 weeks. Accordingly, feeding rats HFD significantly increased body and liver weights, hepatic and serum lipid levels, glucose, insulin, HOMA-IR, liver function enzymes, and inflammation markers, and decreased oxidative stress enzymes. Oral administration of Barhi and Ruthana date seed extracts significantly decreased body and liver weights. Serum and liver total cholesterol TC, Triglycerides TGs, and free fatty acids FFAs were also decreased as were AST, ALT, MAD, leptin, and CRP, with a concomitant increase in SOD, GSH, and CAT. Furthermore, similar to Lipitor, oral administration of the extracts reduced inflammation markers such as TNF-α, serum CRP, IL-6, IL-1β, and leptin while increasing IL-10 and adiponectin levels. Histological observation revealed that extract administration improved hepatocyte and parenchymal structures and decreased lipid deposition. In conclusion, both Barhi and Ruthana seed extracts showed strong hepatoprotective, anti-inflammatory, and antioxidant effects against HFD-induced liver steatosis. And date seeds have other beneficial potential for prevention and treatment of various diseases, which can be studied in the future.

Yinchenhao Tang alleviates high fat diet induced NAFLD by increasing NR1H4 and APOA1 expression.

Traditional Chinese medicine Yinchenhao Tang (YCHT) demonstrated benefits when treating nonalcoholic fatty liver disease (NAFLD), but the dose effects and potential targets are still ambiguous. In this study, different concentrations of YCHT were employed to treat NAFLD and the underlying therapeutic targets were investigated. Kunming mice were fed with high fat diet (HFD) for 8 weeks to induce NAFLD, then treated with 3 different concentrations of YCHT. Hepatic pathological changes and serum lipid levels were examined. Network pharmacology was applied to screen the potential targets of YCHT for NAFLD modulation. NR1H4 and APOA1 expression was evaluated by QPCR and western blotting. Immunohistochemistry (IHC) staining was conducted to visualize the localization pattern of NR1H4 and APOA1 in the liver. YCHT significantly reduced liver lipid storage and improved the liver pathological status of NAFLD mice. The serum lipid levels, as well as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, were remarkably reduced by the middle and high dose YCHT. There are 35 potential targets for YCHT to regulate NAFLD. HFD suppressed both RNA and protein expression of NR1H4 and APOA1, while YCHT elevated NR1H4 and APOA1 expression. IHC staining indicated that NR1H4 was mainly located in the cell nucleus and the APOA1 signal was observed at the liver sinusoid or cytoplasm. YCHT can effectively ameliorate HFD induced NAFLD by modulating the promising targets of NR1H4 and APOA1.

Combined effects of high-fat diet and polystyrene microplastic exposure on microplastic bioaccumulation and lipid metabolism in zebrafish.

Extensive use of microplastics (MPs) threatens the safety of aquatic environments and hydrobionts. Increasing the weight of economic fish through high-fat diet (HFD) to increase production is common in aquaculture. However, little is known about the combined effects of MPs and HFD in fish. The aim of this study was to investigate the relationship between adiposity and MP bioaccumulation in fish. Using zebrafish as a vertebrate model, the content of polystyrene (PS) MPs in zebrafish tissues exposed to 5 and 50μm of 1000μg/L PS MPs was detected via confocal Raman spectroscopy in normal diet (ND) and HFD. The content of PS MPs in HFD group was significantly higher than that in ND group. The levels of hepatic lipids were significantly elevated in zebrafish subjected to HFD treatment, and this effect was aggravated by exposure to 5μmPS MPs, and even caused liver injury. Transcriptomic analysis revealed that exposure to PS MPs interferes with hepatic lipid metabolism and energy homeostasis in zebrafish. These results suggests that in addition to controlling the use and performing proper recycling of plastic products in our daily life, we should not blindly increase the weight of fish through HFD. This aids protect the quality of economic fish and prevent MPs from being consumed by humans through the food chain. This study explored the interaction between fish feed culture and environmental pollutants to provide important reference for fish culture.

Resveratrol supplementation or diet intervention effects on heart-liver axis in prediabetic female rats submitted to high-fat-high-sucrose diet

NAFLD and type 2 diabetes (T2D) share a bidirectional relationship and cardiovascular diseases (CVD) as leading death cause, but this relationship in prediabetes is still poorly known, especially for women which exhibit an exacerbated CVD risk. Here, we evaluated the effects of resveratrol supplementation (RSV) or diet intervention on the heart-liver axis of prediabetic female rats submitted to high-fat-high-sucrose diet (HFS). Forty Female Wistar rats were divided into 4 groups fed for 5 months with: a standard diet (CTRL), HFS diet (HFS), HFS diet supplemented for the last 2 months with RSV (1 mg/kg/day in water) (RSV) or HFS diet for 3 months followed by 2 months of standard diet (RSD). In vivo Magnetic Resonance Imaging was performed to study cardiac morphology/function. Then, tolerance to ischemia-reperfusion injury was investigated ex vivo by simultaneous measurement of cardiac function (RPP, EDP) and energy metabolism by 31P Magnetic Resonance Spectroscopy. Hepatic total lipid and triglycerides (TG) contents along expression of genes involved in lipid metabolism/inflammation were studied. HFS induced glucose intolerance (P < 0.01), increased diastolic left ventricular volume and thickness (P < 0.05) and heart weight to tibia length ratio (HTLR) (P < 0.01). HFS diet also altered myocardial tolerance to IR, with impaired RPP and EDP (P < 0.001) and PCr during reperfusion (P < 0.05). Both treatments improved glucose tolerance (P < 0.05). Importantly, despite maintained HFS diet, RSV restored the elevated diastolic volume and thickness in vivo (P < 0.01 CTRL, RSV vs. HFS, RSD) and HTLR level (P < 0.001 CTRL, RSV vs. HFS, RSD), conversely to RSD. Both treatments improved the tolerance to IR, with increased RPP (P < 0.05 vs. HFS) along with PCr during reperfusion (P < 0.001, P < 0.01 vs. HFS respectively). Only RSV decreased EDP during IR injury (P < 0.05). In the liver HFS diet induced total lipid and TG accumulation (P < 0.01) as well as elevated expression of lipid oxidation/peroxidation genes without effect on lipogenesis and inflammation cytokines genes. Both treatments normalized hepatic total lipid levels. RSD restored TG levels along elevated lipid metabolism gene expressions (P < 0.01) whereas RSV partially reduced the increase (P < 0.05). Despite maintained HFS and moderate hepatic lipid metabolism effects, RSV exhibited better cardioprotection than RSD, suggesting its potential to protect against early cardiac alterations associated with prediabetes and NAFLD, especially for women.

Endotoxin Tolerance Acquisition and Altered Hepatic Fatty Acid Profile in Aged Mice.

(1) Background: Aging is linked to an altered immune response and metabolism. Inflammatory conditions, such as sepsis, COVID-19, and steatohepatitis are more prevalent in the elderly and steatosis is linked both to severe COVID-19 and sepsis. We hypothesized that aging is linked to a loss of endotoxin tolerance, which normally protects the host from excessive inflammation, and that this is accompanied by elevated levels of hepatic lipids. (2) Methods: An in vivo lipopolysaccharide (LPS) tolerance model in young and old mice was used and the cytokine serum levels were measured by ELISA. Cytokine and toll-like receptor gene expression was determined by qPCR in the lungs and the liver; hepatic fatty acid composition was assessed by GC-MS. (3) Results: The old mice showed a distinct potential for endotoxin tolerance as suggested by the serum cytokine levels and gene expression in the lung tissue. Endotoxin tolerance was less pronounced in the livers of the aged mice. However, the fatty acid composition strongly differed in the liver tissues of the young and old mice with a distinct change in the ratio of C18 to C16 fatty acids. (4) Conclusions: Endotoxin tolerance is maintained in advanced age, but changes in the metabolic tissue homeostasis may lead to an altered immune response in old individuals.

Dietary Monounsaturated and Polyunsaturated Fatty Acids are Comparable in their Effects on Hepatic Apolipoprotein mRNA Abundance and Liver Lipid Concentrations when Substituted for Saturated Fatty Acids in Cynomolgus Monkeys

Although studies have shown that saturated and polyunsaturated fats can mediate plasma lipid and apolipoprotein (apo) concentrations at the mRNA level, there is little data on the role of monounsaturated fats. We determined hepatic lipid and apo mRNA levels in 10 cynomolgus monkeys fed three diets that provided 30% of energy as fat with 0.1% cholesterol by weight and differed solely by the substitution of saturated, mono- and polyunsaturated fats as 60% of total fat energy. Total, LDL, and HDL cholesterol, as well as LDL apo B, HDL apo A-I and HDL total apo C concentrations, were reduced with the mono- and polyunsaturated fat diets relative to the saturated fat diet. Although fat saturation did not significantly affect hepatic apo A-I, B, C-II, or E mRNA abundance, hepatic apo C-III mRNA concentrations were uniformly lower (-23%, P < 0.01) with the mono- and polyunsaturated fat diets than with the saturated fat diet. Interestingly, liver triglycerides were significantly elevated with the monounsaturated fat diet relative to the saturated fat diet, but no other differences in hepatic lipids were noted among diets. Hepatic triglyceride composition was shown to reflect dietary fatty acid composition, with liver triglycerides enriched in myristic and palmitic fatty acids during the saturated fat diet, oleic acid during the monounsaturated fat diet and linoleic acid during the polyunsaturated fat diet. We conclude that dietary monounsaturated fats are comparable to polyunsaturated fats in their effects on hepatic lipid and apo mRNA levels in this species, with both unsaturated fats significantly reducing only hepatic apo C-III mRNA abundance relative to saturated fat.

Albumin-fused long-acting FGF21 analogue for the treatment of non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) currently affects about 25% of the world's population, and the numbers continue to rise as the number of obese patients increases. However, there are currently no approved treatments for NAFLD. This study reports on the evaluation of the therapeutic effect of a recombinant human serum albumin-fibroblast growth factor 21 analogue fusion protein (HSA-FGF21) on the pathology of NAFLD that was induced by using two high-fat diets (HFD), HFD-60 and STHD-01. The HFD-60-induced NAFLD model mice with obesity, insulin resistance, dyslipidemia and hepatic lipid accumulation were treated with HSA-FGF21 three times per week for 4weeks starting at 12weeks after the HFD-60 feeding. The administration of HSA-FGF21 suppressed the increased body weight, improved hyperglycemia, hyperinsulinemia, and showed a decreased accumulation of plasma lipid and hepatic lipid levels. The elevation of C16:0, C18:0 and C18:1 fatty acids in the liver that were observed in the HFD-60 group was recovered by the HSA-FGF21 administration. The increased expression levels of the hepatic fatty acid uptake receptor (CD36) and fatty acid synthase (SREBP-1c, FAS, SCD-1, Elovl6) were also suppressed. In adipose tissue, HSA-FGF21 caused an improved adipocyte hypertrophy, a decrease in the levels of inflammatory cytokines and induced the expression of adiponectin and thermogenic factors. The administration of HSA-FGF21 to the STHD-01-induced NAFLD model mice resulted in suppressed plasma ALT and AST levels, oxidative stress, inflammatory cell infiltration and fibrosis. Together, HSA-FGF21 has some potential for use as a therapeutic agent for the treatment of NAFLD.

Impact of different processing mulberry leaf on growth, metabolism and liver immune function of largemouth bass (Micropterus salmoides)

Mulberry leaf is abundant in bioactive ingredients, and their release could be affected by different treatment technologies. In this study, the mulberry leaf was treated with methods of superfine grinding (MG), wall-broken (MB), and water extraction-methanol precipitation (ME). Three processing mulberry leaves were equally added to the feed of largemouth bass (Micropterus salmoides), respectively, and the growth, liver health and intestinal microorganisms were analyzed. According to statistical analysis, the growth of the three experimental groups was remarkedly better than that of the control group fed with a basic diet. The MB group had a higher specific growth rate (SGR) and weight gain rate (WGR) than the MG and ME groups. Mulberry leaf supplementation could significantly reduced blood glucose and serum total cholesterol (TC), very low-density lipoprotein (VLDL) and triglyceride (TG) levels, improved hepatic glycogen, lipid and TG levels, and these parameter values of the MB group were superior to the other treatments. Additionally, MB treatment could up-regulate the expressions of gpx and cat in the liver compared with the control and boost the activities of antioxidant enzymes (GSH-Px and CAT). Meanwhile, MB supplementation suppressed the expressions of pro-inflammatory cytokines (TNFα and IL-8) and up-regulated anti-inflammatory cytokines (IL-10 and TGF-β) in liver compared to the control group. Accordingly, the hepatic histostructure showed an improvement in the treatment group, and mulberry leaf could also dramatically lower the apoptosis of hepatic cells, particularly in the MB group. Furthermore, MB treatment reduced gut dysbiosis by limiting the development of gram-negative and possibly dangerous bacteria. In sum, this study firstly disclosed that the biological effectiveness of mulberry leaf might be impacted by various processing techniques. Especially MB-treatment effectively ameliorates glucose, lipid metabolism and liver immunology in largemouth bass.

Lack of GPR180 ameliorates hepatic lipid depot via downregulation of mTORC1 signaling

Our previous genome-wide association study to explore genetic loci associated with lean nonalcoholic fatty liver disease (NAFLD) in Japan suggested four candidate loci, which were mapped to chr6, chr7, chr12 and chr13. The present study aimed to identify the locus involved functionally in NAFLD around the association signal observed in chr13. Chromosome conformation capture assay and a database survey suggested the intermolecular interaction among DNA fragments in association signals with the adjacent four coding gene promoters. The four genes were further screened by knockdown (KD) in mice using shRNA delivered by an adeno-associated virus vector (AAV8), and KD of G protein-coupled receptor 180 (Gpr180) showed amelioration of hepatic lipid storage. Gpr180 knockout (KO) mice also showed ameliorated hepatic and plasma lipid levels without influencing glucose metabolism after high-fat diet intake. Transcriptome analyses showed downregulation of mTORC1 signaling and cholesterol homeostasis, which was confirmed by weakened phosphorylation of mTOR and decreased activated SREBP1 in Gpr180KO mice and a human hepatoma cell line (Huh7). AAV8-mediated hepatic rescue of GPR180 expression in KO mice showed recovery of plasma and hepatic lipid levels. In conclusion, ablation of GPR180 ameliorated plasma and hepatic lipid levels, which was mediated by downregulation of mTORC1 signaling.

Heating-mediated purification of active FGF21 and structure-based design of its variant with enhanced potency

Fibroblast growth factor 21 (FGF21) has pharmaceutical potential against obesity-related metabolic disorders, including non-alcoholic fatty liver disease. Since thermal stability is a desirable factor for therapeutic proteins, we investigated the thermal behavior of human FGF21. FGF21 remained soluble after heating; thus, we examined its temperature-induced structural changes using circular dichroism (CD). FGF21 showed inter-convertible temperature-specific CD spectra. The CD spectrum at 100 °C returned to that at 20 °C when the heated FGF21 solution was cooled. Through loop swapping, the connecting loop between β10 and β12 in FGF21 was revealed to be associated with the unique thermal behavior of FGF21. According to surface plasmon resonance (SPR) experiments, in vitro cell-based assays, and model high-fat diet (HFD)-induced obesity studies, heated FGF21 maintained biological activities that were comparable to those of non-heated and commercial FGF21s. Based on sequence comparison and structural analysis, five point-mutations were introduced into FGF21. Compared with the wild type, the heated FGF21 variant displayed improved therapeutic potential in terms of body weight loss, the levels of hepatic triglycerides and lipids, and the degree of vacuolization of liver in HFD-fed mice.