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The growth of the aquaculture industry requires more sustainable and circular economy-driven aquafeed formulas. Thus, the goal of the present study was to assess in farmed gilthead sea bream (Sparus aurata L.) how different combinations of novel and conventional fish feed ingredients supported proper animal performance in terms of growth and physiological biomarkers of blood/liver/head kidney. A 77-day feeding trial was conducted with three experimental diets (PAP, with terrestrial processed animal protein from animal by-products; NOPAP, without processed animal protein from terrestrial animal by-products; MIX, a combination of alternative ingredients of PAP and NOPAP diets) and a commercial-type formulation (CTRL), and their effects on growth performance and markers of endocrine growth regulation, lipid metabolism, antioxidant defense and inflammatory condition were assessed at circulatory and tissue level (liver, head kidney). Growth performance was similar among all dietary treatments. However, fish fed the PAP diet displayed a lower feed conversion and protein efficiency, with intermediate values in MIX-fed fish. Such gradual variation in growth performance was supported by different biomarker signatures that delineated a lower risk of oxidation and inflammatory condition in NOPAP fish, in concurrence with an enhanced hepatic lipogenesis that did not represent a risk of lipoid liver degeneration.

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AIMS: This study sought to explore the impact of Fusobacterium nucleatum on hepatic steatosis in apolipoprotein E (ApoE) knockout (KO) mice induced by a high-fat diet (HFD) and elucidate the underlying mechanism. METHODS: ApoE KO mice, on a HFD, received F. nucleatum oral inoculation every other day. After 24 weeks, body weight, liver weight, and liver index were assessed. Serum biochemistry and pro-inflammatory factors in serum and liver were analyzed. The histopathology of right maxilla and live were performed. Oil red O, immunohistochemistry, and immunofluorescence staining for the liver were conducted. Myeloperoxidase (MPO) activity, apoptosis, lipid reactive oxygen species (ROS), ROS, lipid peroxides, and hepatic lipids were also evaluated. Liver inflammation, fibrosis, de novo lipogenesis (DNL)-related molecule, and Nrf2/Keap1-related signaling molecule gene/protein expression were determined by real-time PCR (RT-PCR) and/or Western blot (WB) analysis. RESULTS: HFD-fed ApoE KO mice infected by F. nucleatum demonstrated significant changes, including increased body and liver weight, elevated proinflammatory factors and lipids in serum and liver, as well as neutrophil infiltration, fibrosis, apoptosis, oxidative stress, and lipid peroxidation in the liver. Additionally, F. nucleatum stimulates hepatic lipid accumulation and activates de novo lipogenesis (DNL), while simultaneously suppressing the Nrf2/Keap1 antioxidant pathway. CONCLUSION: In conclusion, our study reveals that oral inoculation of F. nucleatum might promote hepatic steatosis by inhibiting Nrf2/Keap1 pathway.

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BACKGROUND: The mitochondria-associated endoplasmic reticulum membrane (MAM) is the central hub for endoplasmic reticulum and mitochondria functional communication. It plays a crucial role in hepatic lipid homeostasis. However, even though MAM has been acknowledged to be rich in enzymes that contribute to lipid biosynthesis, no study has yet investigated the exact role of MAM on hepatic neutral lipid synthesis. OBJECTIVES: To address these gaps, this study investigated the systemic control mechanisms of MAM on neutral lipids synthesis by recruiting seipin, focusing on the role of the inositol trisphosphate receptor-1,4,5(Ip3r)-75 kDa glucose-regulated protein (Grp75)-voltage-dependent anion channel (Vdac) complex and their relevant Ca2+ signaling in this process. METHODS: To this end, a model animal for lipid metabolism, yellow catfish (Pelteobagrus fulvidraco), were fed 6 different diets containing a range of palmitic acid (PA) concentrations from 0-150 g/kg in vivo for 10 wk. In vitro, experiments were also conducted to intercept the MAM-mediated Ca2+ signaling in isolated hepatocytes by transfecting them with si-mitochondrial calcium uniporter (mcu). Because mcu was placed in the inner mitochondrial membrane (IMM), si-mcu cannot disrupt MAM's structural integrity. RESULTS: 1. Hepatocellular MAM subproteome analysis indicated excessive dietary PA intake enhanced hepatic MAM structure joined by activating Ip3r-Grp75-Vdac complexes. 2. Dietary PA intake induced hepatic neutral lipid accumulation through MAM recruiting Seipin, which activated lipid droplet biogenesis. Our findings also revealed a previously unidentified mechanism whereby MAM-recruited seipin and controlled hepatic lipid homeostasis, depending on Ip3r-Grp75-Vdac-controlled Ca2+ signaling and not only MAM's structural integrity. CONCLUSIONS: These results offer a novel insight into the MAM-recruited seipin in controlling hepatic lipid synthesis in a MAM structural integrity-dependent and Ca2+ signaling-dependent manner, highlighting the critical contribution of MAM in maintaining hepatic neutral lipid homeostasis.

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BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Aberrant lipid metabolism and accumulation of extracellular matrix proteins are hallmarks of the disease, but the underlying mechanisms are largely unknown. This study aims to elucidate the key role of sine oculis homeobox homologue 1 (SIX1) in the development of NAFLD. METHODS: Alb-Cre mice were administered the AAV9 vector for SIX1 liver-specific overexpression or knockdown. Metabolic disorders, hepatic steatosis, and inflammation were monitored in mice fed with HFHC or MCD diet. High throughput CUT&Tag analysis was employed to investigate the mechanism of SIX1 in diet-induced steatohepatitis. RESULTS: Here, we found increased SIX1 expression in the livers of NAFLD patients and animal models. Liver-specific overexpression of SIX1 using adeno-associated virus serotype 9 (AAV9) provoked more severe inflammation, metabolic disorders, and hepatic steatosis in the HFHC or MCD-induced mice model. Mechanistically, we demonstrated that SIX1 directly activated the expression of liver X receptor α (LXRα) and liver X receptor ß (LXRß), thus inducing de novo lipogenesis (DNL). In addition, our results also illustrated a critical role of SIX1 in regulating the TGF-ß pathway by increasing the levels of type I and II TGF-ß receptor (TGFßRI/TGFßRII) in hepatic stellate cells (HSCs). Finally, we found that liver-specific SIX1 deficiency could ameliorate diet-induced NAFLD pathogenesis. CONCLUSION: Our findings suggest a detrimental function of SIX1 in the progression of NAFLD. The direct regulation of LXRα/ß and TGF-ß signalling by SIX1 provides a new regulatory mechanism in hepatic steatosis and fibrosis.

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AIMS: Positive associations between periodontitis (PD) and atherosclerosis have been established, but the causality and mechanisms are not clear. We aimed to explore the causal roles of PD in atherosclerosis and dissect the underlying mechanisms. METHODS AND RESULTS: A mouse model of PD was established by ligation of molars in combination with application of subgingival plaques collected from PD patients and then combined with atherosclerosis model induced by treating atheroprone mice with a high-cholesterol diet (HCD). PD significantly aggravated atherosclerosis in HCD-fed atheroprone mice, including increased en face plaque areas in whole aortas and lesion size at aortic roots. PD also increased circulating levels of triglycerides and cholesterol, hepatic levels of cholesterol, and hepatic expression of rate-limiting enzymes for lipogenesis. Using 16S ribosomal RNA (rRNA) gene sequencing, Fusobacterium nucleatum was identified as the most enriched PD-associated pathobiont that is present in both the oral cavity and livers. Co-culture experiments demonstrated that F. nucleatum directly stimulated lipid biosynthesis in primary mouse hepatocytes. Moreover, oral inoculation of F. nucleatum markedly elevated plasma levels of triglycerides and cholesterol and promoted atherogenesis in HCD-fed ApoE-/- mice. Results of RNA-seq and Seahorse assay indicated that F. nucleatum activated glycolysis, inhibition of which by 2-deoxyglucose in turn suppressed F. nucleatum-induced lipogenesis in hepatocytes. Finally, interrogation of the molecular mechanisms revealed that F. nucleatum-induced glycolysis and lipogenesis by activating PI3K/Akt/mTOR signalling pathway in hepatocytes. CONCLUSIONS: PD exacerbates atherosclerosis and impairs lipid metabolism in mice, which may be mediated by F. nucleatum-promoted glycolysis and lipogenesis through PI3K/Akt/mTOR signalling in hepatocytes. Treatment of PD and specific targeting of F. nucleatum are promising strategies to improve therapeutic effectiveness of hyperlipidaemia and atherosclerosis.

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A high-fructose diet (HFD) induces murine alterations like those recorded in human prediabetes. Protective effects of isoespintanol (monoterpene isolated from Oxandra cf. xylopioides) on changes induced by HFD were evaluated. Animals were maintained for 21 days with a standard diet (C), 10% fructose (F), and F plus isoespintanol (FI, 10 mg/kg, i.p.). Glycemia, triglyceridemia, total and HDL-cholesterol, and insulin resistance index (IRX) were determined. Intraperitoneal glucose tolerance test (IGTT) was performed. In the liver, we measured glycogen, lipogenic gene expression (SREBP-1c, GPAT, FAS, and CPT1), oxidative stress (GSH and 3'-nitrotyrosine content), inflammation markers (iNOS, TNF-α, and PAI-1 gene expression; iNOS and COX-2 protein levels), p-eNOS, p-Akt, and p-GSK3ß protein levels. Isoespintanol corrected enhanced triglycerides, lipogenic genes, and IRX, and reduced HDL-cholesterol induced by HFD. Increased liver glycogen and inflammatory markers and decreased GSH, p-Akt, and p-GSK3ß measured in F rats were reversed by isoespintanol, and p-eNOS/e-NOS and iNOS/GADPH ratios were normalized. Isoespintanol restored glucose tolerance (IGTT) compared to F rats. These results demonstrate for the first time that isoespintanol prevents endocrine-metabolic alterations induced by HFD in prediabetic rats. These effects could be mediated by Akt/eNOS and Akt/GSK3ß pathways, suggesting its possible use as a therapeutic tool for the prevention of diabetes at early stages of its development (prediabetes).

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Long non-coding RNAs (lncRNAs) are known to play crucial roles in nonalcoholic fatty liver disease (NAFLD). This research sought to explore mechanisms by which lncRNA MALAT1 regulates the progression of NAFLD. Thus, in order to detect the function of MALAT1 in NAFLD, in vitro and in vivo model of NAFLD were established. Then, fatty acid uptake and triglyceride level were investigated by BODIPY labeled-fatty acid uptake assay and Oil red O staining, respectively. The expressions of MALAT1, miR-206, ARNT, PPARα and CD36 were detected by western blotting and qPCR. Dual luciferase, RIP and ChIP assay were used to validate the relation among MALAT1, miR-206, ARNT and PPARα. The data revealed expression of MALAT1 was up-regulated in vitro and in vivo in NAFLD, and knockdown of MALAT1 suppressed FFA-induced lipid accumulation in hepatocytes. Meanwhile, MALAT1 upregulated the expression of ARNT through binding with miR-206. Moreover, miR-206 inhibitor reversed MALAT1 knockdown effects in decreased lipid accumulation in FFA-treated hepatocytes. Furthermore, ARNT could inhibit the expression of PPARα via binding with PPARα promoter. Knockdown of MALAT1 significantly upregulated the level of PPARα and downregulated the expression of CD36, while PPARα knockdown reversed these phenomena. MALAT1 regulated PPARα/CD36 -mediated hepatic lipid accumulation in NAFLD through regulation of miR-206/ARNT axis. Thus, MALAT1/miR-206/ARNT might serve as a therapeutic target against NAFLD.

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Dysregulated hepatic lipogenesis represents a promising druggable target for treating nonalcoholic steatohepatitis (NASH). This work aims to evaluate the therapeutic efficacy of caffeine in a NASH mouse model displaying increased hepatic lipogenesis driven by constitutive hepatic overexpression of the active v-akt murine thymoma viral oncogene homolog (AKT). Caffeine was administered in the AKT mice to study the efficacy in vivo. AKT-transfected and insulin-stimulated human hepatoma cells were used for in vitro experiments. The results demonstrated that caffeine ameliorated hepatic steatosis and inflammatory injury in vivo. Mechanistically, caffeine repressed the AKT/mTORC1 and SREBP-1/ACC/FASN signaling in mice and in vitro. Furthermore, caffeine impaired NF-κB activation by stabilizing IκBα, resulting in a reduction of proinflammatory mediators interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α). Notably, caffeine abolished mTORC1/FASN-dependent MyD88 palmitoylation, which could be essential for its anti-inflammatory potential. Collectively, these results suggest that caffeine consumption could be advantageous in the prevention and therapy of NASH, especially in the subset accompanied by increased de novo lipogenesis.

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Alstonia scholaris (L.) R. Br (Apocynaceae) is a well-documented medicinal plant for treating respiratory diseases, liver diseases and diabetes traditionally. The current study aimed to investigate the effects of TA on non-alcoholic fatty liver disease (NAFLD). A NAFLD model was established using mice fed a high-fat diet (HFD) and administered with TA (7.5, 15 and 30 mg/kg) orally for 6 weeks. The biochemical parameters, expressions of lipid metabolism-related genes or proteins were analyzed. Furthermore, histopathological examinations were evaluated with Hematoxylin-Eosin and MASSON staining. TA treatment significantly decreased the bodyweight of HFD mice. The concentrations of low-density lipoprotein (LDL), triglyceride (TG), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were also decreased significantly in TA-treated mice group, accompanied by an increase in high-density lipoprotein (HDL). Furthermore, TA alleviated hepatic steatosis injury and lipid droplet accumulation of liver tissues. The liver mRNA levels involved in hepatic lipid synthesis such as sterol regulatory element-binding protein 1C (SREBP-1C), regulators of liver X receptor α (LXRα), peroxisome proliferator activated receptor (PPAR)γ, acetyl-CoA carboxylase (ACC1) and stearyl coenzyme A dehydrogenase-1 (SCD1), were markedly decreased, while the expressions involved in the regulation of fatty acid oxidation, PPARα, carnitine palmitoyl transterase 1 (CPT1A), and acyl coenzyme A oxidase 1 (ACOX1) were increased in TA-treated mice. TA might attenuate NAFLD by regulating hepatic lipogenesis and fatty acid oxidation.

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Regulating dietary fat absorption may impact progression of nonalcoholic fatty liver disease (NAFLD). Here, we asked if inducible inhibition of chylomicron assembly, as observed in intestine-specific microsomal triglyceride (TG) transfer protein knockout mice (Mttp-IKO), could retard NAFLD progression and/or reverse established fibrosis in two dietary models. Mttp-IKO mice fed a methionine/choline-deficient (MCD) diet exhibited reduced hepatic TGs, inflammation, and fibrosis, associated with reduced oxidative stress and downstream activation of c-Jun N-terminal kinase and nuclear factor kappa B signaling pathways. However, when Mttpflox mice were fed an MCD for 5 weeks and then administered tamoxifen to induce Mttp-IKO, hepatic TG was reduced, but inflammation and fibrosis were increased after 10 days of reversal along with adaptive changes in hepatic lipogenic mRNAs. Extending the reversal time, following 5 weeks of MCD feeding to 30 days led to sustained reductions in hepatic TG, but neither inflammation nor fibrosis was decreased, and both intestinal permeability and hepatic lipogenesis were increased. In a second model, similar reductions in hepatic TG were observed when mice were fed a high-fat/high-fructose/high-cholesterol (HFFC) diet for 10 weeks, then switched to chow ± tamoxifen (HFFC → chow) or (HFFC → Mttp-IKO chow), but again neither inflammation nor fibrosis was affected. In conclusion, we found that blocking chylomicron assembly attenuates MCD-induced NAFLD progression by reducing steatosis, oxidative stress, and inflammation. In contrast, blocking chylomicron assembly in the setting of established hepatic steatosis and fibrosis caused increased intestinal permeability and compensatory shifts in hepatic lipogenesis that mitigate resolution of inflammation and fibrogenic signaling despite 50-90-fold reductions in hepatic TG.

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BACKGROUND AND AIMS: Butyric acid is an intestinal microbiota-produced short-chain fatty acid, which exerts salutary effects on alleviating nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism of butyrate on regulating hepatic lipid metabolism is largely unexplored. METHODS: A mouse model of NAFLD was induced with high-fat diet feeding, and sodium butyrate (NaB) intervention was initiated at the eighth week and lasted for 8 weeks. Hepatic steatosis was evaluated and metabolic pathways concerning lipid homeostasis were analyzed. RESULTS: Here, we report that administration of NaB by gavage once daily for 8 weeks causes an augmentation of insulin-induced gene (Insig) activity and inhibition of lipogenic gene in mice fed with high-fat diet. Mechanistically, NaB is sufficient to enhance the interaction between Insig and its upstream kinase AMP-activated protein kinase (AMPK). The stimulatory effects of NaB on Insig-1 activity are abolished in AMPKα1/α2 double knockout (AMPK-/-) mouse primary hepatocytes. Moreover, AMPK activation by NaB is mediated by LKB1, as evidenced by the observations showing NaB-mediated induction of phosphorylation of AMPK, and its downstream target acetyl-CoA carboxylase is diminished in LKB1-/- mouse embryonic fibroblasts. CONCLUSIONS: These studies indicate that NaB serves as a negative regulator of hepatic lipogenesis in NAFLD and that NaB attenuates hepatic steatosis and improves lipid profile and liver function largely through the activation of LKB1-AMPK-Insig signaling pathway. Therefore, NaB has therapeutic potential for treating NAFLD and related metabolic diseases.

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Diets enriched with phytogenic feed additives (PFA) such as AV/HGP/16 premix (AVHGP), Superliv concentrate premix (SCP), and bacteriostatic herbal growth promotor (BHGP) with essential oils have been shown to improve feed efficiency (FE) in broilers. This FE improvement was achieved via modulation of hypothalamic neuropeptides, which results despite feed intake reduction, in increased breast yield without changes in body weight compared to the control group. To gain further insights into the mode of action of these PFA, the present study aimed to determine the potential involvement of signaling pathways associated with lipid and protein metabolism. One day-old male Cobb 500 chicks were randomly assigned into 1 of 4 treatments, comprising 8 replicates per treatment in a completely randomized design. The dietary treatments included a basal diet (control) or 0.55 g/kg diet of AVHGP, SCP, or BHGP. The birds had ad libitum access to water and feed. On day 35, after blood sampling, the liver, abdominal adipose tissue (AT), and breast muscle samples were collected. The levels of phosphorylated mechanistic target of rapamycin (mTOR)Ser2481 as well as its levels of mRNA and those of its downstream mediator RPS6B1 were significantly upregulated in the muscle of the PFA-fed groups compared with the control group. In the liver, the phosphorylated levels of acetyl-CoA carboxylase alpha at Ser79, the rate-limiting enzyme in fat synthesis, was significantly induced in the PFA-fed groups compared with the control group, indicating a lower hepatic lipogenesis. The hepatic expression of hepatic triglyceride lipase (LIPC) and adipose triglyceride lipase (ATGL) was significantly upregulated in the AVHGP-fed group compared with the control group. These hepatic changes were accompanied by a significant downregulation of hepatic sterol regulatory element-binding protein cleavage-activating protein in all the PFA groups and an upregulation of peroxisome proliferator-activated receptor alpha and gamma in the SCP-fed compared with the control group. In the AT, the mRNA abundances of ATGL and LIPC were significantly increased in both SCP- and BHGP-fed birds compared with the control group. Together these data indicate that PFA improve FE via modulation of muscle mTOR pathway and hepatic lipolytic/lipogenic programs, thus, favoring muscle protein synthesis and lowering hepatic lipogenesis.

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Human sex hormone-binding globulin (SHBG) is a glycoprotein produced by the liver that binds sex steroids with high affinity and specificity. Clinical observations and reports in the literature have suggested a negative correlation between circulating SHBG levels and markers of non-alcoholic fatty liver disease (NAFLD) and insulin resistance. Decreased SHBG levels increase the bioavailability of androgens, which in turn leads to progression of ovarian pathology, anovulation and the phenotypic characteristics of polycystic ovarian syndrome (PCOS). This review will use a case report to illustrate the inter-relationships between SHBG, NAFLD and PCOS. In particular, we will review the evidence that low hepatic SHBG production may be a key step in the pathogenesis of PCOS. Furthermore, there is emerging evidence that serum SHBG levels may be useful as a diagnostic biomarker and therapeutic target for managing women with PCOS.

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In this study, we prepared palatinose-sucrose (PS) mixtures from sucrose by enzymatic bioconversion to improve the low sweetness of palatinose and to develop sweeteners that can lower blood sugar levels. We hypothesized that PS mixtures containing 30% or 50% palatinose might demonstrate improvement of hyperglycemia. The physiological changes in C57BL/6J mice fed with these concentrations of PS mixture were recorded. After feeding the mice the different diets for 5 weeks, the diet with a higher palatinose content was observed to have resulted in lower serum glucose levels. The expression levels of various genes and proteins related to hepatic lipogenesis and cholesterol homeostasis were measured. The diet containing the 50% PS mixture induced lower expression of HMGCR, CYP7A1, and PPARγ as compared to the diet containing the 30% PS mixture. In conclusion, the ingestion of palatinose resulted in lower lipid levels compared to that of sucrose; therefore, palatinose would be a good alternative to sucrose as a healthy sweetener. PRACTICAL APPLICATIONS: Palatinose (isomaltulose), along with tagatose, allulose, and allose, is a well-known sugar substitute. Many studies have reported that palatinose has various beneficial effects on postprandial glucose metabolism, such as glycemic index, fat accumulation, hyperglycemia, and hyperinsulinemia. Although there are many advantages, including desirable biological functions, palatinose has limitations as a complete alternative for sucrose because of higher production costs, lower solubility, and lower sweetness. Therefore, we aimed to investigate the possibility of developing a sucrose substitute by preparing PS mixtures bioconverted using α-glucosyltransferase from sucrose and to promote the industrial application of palatinose. Our results suggest that 50% palatinose syrup may be a new candidate as a sugar substitute for industrial application.

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Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are associated with hepatic steatosis and insulin resistance. Molecular mechanisms underlying ER stress and/or mitochondrial dysfunction that cause metabolic disorders and hepatic steatosis remain to be fully understood. Here, we found that a high fat diet (HFD) or chemically induced ER stress can stimulate mitochondrial stress protein HSP60 expression, impair mitochondrial respiration, and decrease mitochondrial membrane potential in mouse hepatocytes. HSP60 overexpression promotes ER stress and hepatic lipogenic protein expression and impairs insulin signaling in mouse hepatocytes. Mechanistically, HSP60 regulates ER stress-induced hepatic lipogenesis via the mTORC1-SREBP1 signaling pathway. These results suggest that HSP60 is an important ER and mitochondrial stress cross-talking protein and may control ER stress-induced hepatic lipogenesis and insulin resistance.

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TIR domain-containing adaptor-inducing interferon-ß (TRIF), a cytosolic adaptor protein, plays a key role in the mammalian toll-like receptor-mediated signaling pathway. However, the role of TRIF in large yellow croaker (LcTRIF) remains poorly understood. The main objective of this study was to explore the role of LcTRIF in triggering antiviral immune responses and the potential function of LcTRIF in regulating lipid metabolism. In the present study, the full-length coding sequence of TRIF from large yellow croaker was cloned and characterized. In vivo, upon poly (I:C) stimulation, the transcriptional levels of LcTRIF were rapidly elevated in immune-related tissues at the early stage of injection. In vitro, the MRNA expression of LcTRIF was significantly but not dramatically upregulated in macrophages treated with poly (I:C). Activation of LcTRIF by poly (I:C) significantly increased the transcription of genes involved in inflammatory responses, and this induction was blocked by knockdown of LcTRIF. Moreover, the ability of LcTRIF to induce inflammatory responses may partially be attributed to the promotion of mRNA expression of IFNh and NF-κB pathway genes. In addition, activation of the LcTRIF-mediated pathway inhibited the increase in hepatic stearoyl-coenzyme A (CoA) desaturase 1 induced by palmitic acid and subsequently alleviated lipid accumulation in hepatocytes. These results revealed the crucial role of LcTRIF in triggering antiviral immune responses and the unconventional metabolic function of LcTRIF in regulating hepatic lipogenesis in large yellow croaker.

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The impact of gut microbiota and its metabolites on fat metabolism have been widely reported in human and animals. However, the critical mediators and the signal transductions are not well demonstrated. As ovipara, chicken represents a specific case in lipid metabolism that liver is the main site of lipid synthesis. The aim of this study is to elucidate the linkage of gut microbiota and fat synthesis in broiler chickens. The broilers were subjected to dietary treatments of combined probiotics (Animal bifidobacterium: 4 × 108 cfu/kg; Lactobacillus plantarum: 2 × 108 cfu/kg; Enterococcus faecalis: 2 × 108 cfu/kg; Clostridium butyrate: 2 × 108 cfu/kg, PB) and guar gum (1 g/kg, GG), respectively. Results showed that dietary supplementation of PB and GG changed the cecal microbiota diversity, altered short chain fatty acids (SCFAs) contents, and suppressed lipogenesis. In intestinal epithelial cells (IECs), SCFAs (acetate, propionate, and butyrate) up-regulated the expression of glucagon-like peptide-1 (GLP-1) via mitogen-activated protein kinase (MAPK) pathways, mainly via the phospho - extracellular regulated protein kinase (ERK) and phospho-p38 mitogen activated protein kinase (p38 MAPK) pathways. GLP-1 suppressed lipid accumulation in primary hepatocytes with the involvement of (AMP)-activated protein kinase/Acetyl CoA carboxylase (AMPK/ACC) signaling. In conclusion, the result suggests that SCFAs-induced GLP-1 secretion via MAPK pathway, which links the regulation of gut microbiota on hepatic lipogenesis in chickens.

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Although SREBP-1c regulates key enzymes required for hepatic de novo lipogenesis, the mechanisms underlying transcriptional regulation of SREBP-1c in pathogenesis of alcoholic fatty liver is still incompletely understood. In this study, we investigated the role of ERRγ in alcohol-mediated hepatic lipogenesis and examined the possibility to ameliorate alcoholic fatty liver through its inverse agonist. Hepatic ERRγ and SREBP-1c expression was increased by alcohol-mediated activation of CB1 receptor signaling. Deletion and mutation analyses of the Srebp-1c gene promoter showed that ERRγ directly regulates Srebp-1c gene transcription via binding to an ERR-response element. Overexpression of ERRγ significantly induced SREBP-1c expression and fat accumulation in liver of mice, which were blocked in Srebp-1c-knockout hepatocytes. Conversely, liver-specific ablation of ERRγ gene expression attenuated alcohol-mediated induction of SREBP-1c expression. Finally, an ERRγ inverse agonist, GSK5182, significantly ameliorates fatty liver disease in chronically alcohol-fed mice through inhibition of SREBP-1c-mediated fat accumulation. ERRγ mediates alcohol-induced hepatic lipogenesis by upregulating SREBP-1c expression, which can be blunted by the inverse agonist for ERRγ, which may be an attractive therapeutic strategy for the treatment of alcoholic fatty liver disease in human.

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We investigated the physiological activity of an oil rich in γ-linolenic acid of evening primrose origin (containing 42.6% γ-linolenic acid) affecting hepatic fatty acid metabolism, and serum lipid levels in genetically hyperlipidemic mice deficient in apolipoprotein E expression. Male apolipoprotein E-deficient mice (BALB/c.KOR/StmSlc-Apoe shl ) were fed experimental diets containing 100 g/kg of palm oil (saturated fat), safflower oil (rich in linoleic acid), γ-linolenic acid oil (rich in γ-linolenic acid), or fat mixtures composed of safflower and γ-linolenic acid oils (65:35 and 30:70, w/w) for 20 days. γ-Linolenic acid oil, compared with palm and safflower oils, strongly and dose-dependently increased the activity and mRNA levels of hepatic fatty acid oxidation enzymes. In general, safflower and γ-linolenic acid oils, compared with palm oil, reduced the activity and mRNA levels of lipogenic enzymes. However, these oils were equivalent in reducing the parameters of lipogenesis, excluding malic enzyme and pyruvate kinase. The diets containing safflower and γ-linolenic acid oils, compared with the palm oil diet, significantly decreased serum triacylglycerol and cholesterol levels. The decreases were greater with γ-linolenic acid oil than with safflower oil. γ-Linolenic acid oil exerted strong serum lipid-lowering effects in apolipoprotein E-deficient mice apparently through the changes in hepatic fatty acid metabolism.

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IMPACT STATEMENT: Due to high-fat and high-sugar diets accompanied by sedentary lifestyles, diabetes has become a global epidemic. Literature findings suggest a potential therapeutic effect of Nrg4 on treating obesity-related metabolic disorders including type 2 diabetes (T2D). Adipose tissue-derived MSCs (ADSCs) were used in our study as they are abundant and can be harvested with minimally invasive procedures. In the end, our study reveals that ADSC transplantation improves glucose tolerance and metabolic balance in HFD-fed mice by multiple mechanisms, including upregulating GLUT4 expression and suppressing inflammation. More importantly, our study shows that Nrg4 overexpression could improve the efficacy of ADSCs in ameliorating insulin resistance (IR) and other obesity-related metabolic disorders, given the function of Nrg4 in attenuating hepatic lipogenesis. It would provide a new therapeutic strategy for the treatment of obesity, IR, and T2D.

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