Diet-induced Fatty Liver Research Articles

Insulin-like Growth Factor 2 mRNA-Binding Protein 2-a Potential Link Between Type 2 Diabetes Mellitus and Cancer.

ContextType 2 diabetes mellitus (T2DM) and cancer share a variety of risk factors and pathophysiological features. It is becoming increasingly accepted that the 2 diseases are related, and that T2DM increases the risk of certain malignancies.ObjectiveThis review summarizes recent advancements in the elucidation of functions of insulin-like growth factor 2 (IGF-2) messenger RNA (mRNA)-binding protein 2 (IGF2BP2) in T2DM and cancer.MethodsA PubMed review of the literature was conducted, and search terms included IGF2BP2, IMP2, or p62 in combination with cancer or T2DM. Additional sources were identified through manual searches of reference lists. The increased risk of multiple malignancies and cancer-associated mortality in patients with T2DM is believed to be driven by insulin resistance, hyperinsulinemia, hyperglycemia, chronic inflammation, and dysregulation of adipokines and sex hormones. Furthermore, IGF-2 is oncogenic, and its loss-of-function splice variant is protective against T2DM, which highlights the pivotal role of this growth factor in the pathogenesis of these 2 diseases. IGF-2 mRNA-binding proteins, particularly IGF2BP2, are also involved in T2DM and cancer, and single-nucleotide variations (formerly single-nucleotide polymorphisms) of IGF2BP2 are associated with both diseases. Deletion of the IGF2BP2 gene in mice improves their glucose tolerance and insulin sensitivity, and mice with transgenic p62, a splice variant of IGF2BP2, are prone to diet-induced fatty liver disease and hepatocellular carcinoma, suggesting the biological significance of IGF2BP2 in T2DM and cancer.ConclusionAccumulating evidence has revealed that IGF2BP2 mediates the pathogenesis of T2DM and cancer by regulating glucose metabolism, insulin sensitivity, and tumorigenesis. This review provides insight into the potential involvement of this RNA binding protein in the link between T2DM and cancer.

Identification of Dacinostat as a potential anti-obesity compound through transcriptional activation of adipose thermogenesis in mice

Obesity is a worldwide health problem. Activating fat mobilization and reducing fat synthesis is a promising strategy to mitigate obesity and its complicated metabolic diseases. However, few clinically effective and safe agents conform to the strategy. In the present study, by screening the next-generation L1000-based CMAP small molecule library, we identify histone deacetylase inhibitor Dacinostat, which has been previously tested in clinical trials for patients with advanced solid tumors, as an anti-obesity candidate. Administration of Dacinostat prevents high-fat diet-induced obesity, insulin resistance, and fatty liver in mice without causing adverse effects. Dacinostat treatment enhances adipose thermogenesis as shown by elevated body temperature, accompanied with high mRNA expression of Ucp1 and Ppargc1α. Mechanistically, we show that the thermogenic effect of Dacinostat is achieved by acetylation of histone 3 lysine 27 mediated transcriptional activation of Ucp1 and Ppargc1α in adipose tissue. In conclusion, these findings suggest that Dacinostat is a potential anti-obesity compound through transcriptional activation of adipose thermogenesis.

A mouse model of short-term, diet-induced fatty liver with abnormal cardiolipin remodeling via downregulated Tafazzin gene expression.

Cardiolipin (CL) helps maintain mitochondrial structure and function. Here we investigated whether a high carbohydrate diet (HCD) fed to mice for a short period (5 days) could modulate the CL level, including that of monolysoCL (MLCL) in the liver. Total CL in the HCD group was 22% lower than that in the normal chow diet (NCD) group (P < 0.05). The CL72:8 level strikingly decreased by 93% (P < 0.0001), whereas total nascent CLs (CLs other than CL72:8) increased (P < 0.01) in the HCD group. The total MLCL in the HCD group increased by 2.4-fold compared with that in the NCD group (P < 0.05). Tafazzin expression in the HCD group was significantly downregulated compared with that in the NCD group (P < 0.05). A strong positive correlation between nascent CL and total MLCL (r=0.955, P < 0.0001), and a negative correlation between MLCL and Tafazzin expression (r=-0.593, P=0.0883) were observed. A HCD modulated the fatty acid composition of CL and MLCL via Tafazzin in the liver, which could lead to mitochondrial dysfunction. This model may be useful for elucidating the relationship between fatty liver and mitochondrial dysfunction. © 2021 Society of Chemical Industry.

Lowering apolipoprotein CIII protects against high-fat diet-induced metabolic derangements.

Increased levels of apolipoprotein CIII (apoCIII), a key regulator of lipid metabolism, result in obesity-related metabolic derangements. We investigated mechanistically whether lowering or preventing high-fat diet (HFD)-induced increase in apoCIII protects against the detrimental metabolic consequences. Mice, first fed HFD for 10 weeks and thereafter also given an antisense (ASO) to lower apoCIII, already showed reduced levels of apoCIII and metabolic improvements after 4 weeks, despite maintained obesity. Prolonged ASO treatment reversed the metabolic phenotype due to increased lipase activity and receptor-mediated hepatic uptake of lipids. Fatty acids were transferred to the ketogenic pathway, and ketones were used in brown adipose tissue (BAT). This resulted in no fat accumulation and preserved morphology and function of liver and BAT. If ASO treatment started simultaneously with the HFD, mice remained lean and metabolically healthy. Thus, lowering apoCIII protects against and reverses the HFD-induced metabolic phenotype by promoting physiological insulin sensitivity.

Ahnak deficiency attenuates high-fat diet-induced fatty liver in mice through FGF21 induction

The AHNAK nucleoprotein has been determined to exert an anti-obesity effect in adipose tissue and further inhibit adipogenic differentiation. In this study, we examined the role of AHNAK in regulating hepatic lipid metabolism to prevent diet-induced fatty liver. Ahnak KO mice have reportedly exhibited reduced fat accumulation in the liver and decreased serum triglyceride (TG) levels when provided with either a normal chow diet or a high-fat diet (HFD). Gene expression profiling was used to identify novel factors that could be modulated by genetic manipulation of the Ahnak gene. The results revealed that fibroblast growth factor 21 (FGF21) was markedly increased in the livers of Ahnak KO mice compared with WT mice fed a HFD. Ahnak knockdown in hepatocytes reportedly prevented excessive lipid accumulation induced by palmitate treatment and was associated with increased secretion of FGF21 and the expression of genes involved in fatty acid oxidation, which are primarily downstream of PPARα. These results indicate that pronounced obesity and hepatic steatosis are attenuated in HFD-fed Ahnak KO mice. This may be attributed, in part, to the induction of FGF21 and regulation of lipid metabolism, which are considered to be involved in increased fatty acid oxidation and reduced lipogenesis in the liver. These findings suggest that targeting AHNAK may have beneficial implications in preventing or treating hepatic steatosis.

Duodenal-jejunal bypass maintains hepatic S-adenosylmethionine/S-homocysteine ratio in diet-induced obese rats.

We previously reported that the duodenal-jejunal bypass (DJB) surgery altered transsulfuration and purine metabolism via flux changes in 1-carbon metabolism in the liver. In this study, we extended our study to gain further insight into mechanistic details of how the DJB-induced flux changes in 1-carbon metabolism contributes to the improvement of diet-induced nonalcoholic fatty liver disease. Rodents were subjected to surgical (sham operation and DJB) or dietary (reduced food supply to follow the weight changes in the DJB group) interventions. The microscopic features of the liver were examined by immunohistochemistry. The expressions of genes in lipid synthesis and in 1-carbon cycle in the liver were analyzed by real-time polymerase chain reaction and western blotting. Metabolic changes in the liver were determined. We observed that DJB reduces hepatic steatosis and improves insulin sensitivity in both high-fat diet-fed rats and mice. Metabolic analyses revealed that the possible underlying mechanism may involve decreased S-adenosylmethionine (SAM)-to-S-adenosylhomocysteine ratio via downregulation of SAM synthesizing enzyme and upregulation of SAM catabolizing enzyme. We also found in mice that DJB-mediated attenuation of hepatic steatosis is independent of weight loss. DJB also increased hepatic expression levels of GNMT while decreasing those of PEMT and BHMT, a change in 1-carbon metabolism that may decrease the ratio of SAM to S-adenosylhomocysteine, thereby resulting in the prevention of fat accumulation in the liver. Thus, we suggest that the change in 1-carbon metabolism, especially the SAM metabolism, may contribute to the improvement of diet-induced fatty liver disease after DJB surgery.

FOXA3 induction under endoplasmic reticulum stress contributes to non-alcoholic fatty liver disease

Chronic endoplasmic reticulum (ER) stress in the liver has been shown to play a causative role in non-alcoholic fatty liver disease (NAFLD) progression, yet the underlying molecular mechanisms remain to be elucidated. Forkhead box A3 (FOXA3), a member of the FOX family, plays critical roles in metabolic homeostasis, although its possible functions in ER stress and fatty liver progression are unknown. Adenoviral delivery, siRNA delivery, and genetic knockout mice were used to crease FOXA3 gain- or loss-of-function models. Tunicamycin (TM) and a high-fat diet (HFD) were used to induce acute or chronic ER stress in mice. Chromatin immunoprecipiation (ChIP)-seq, luciferase assay, and adenoviral-mediated downstream gene manipulations were performed to reveal the transcriptional axis involved. Key axis protein levels in livers from healthy donors and patients with NAFLD were assessed via immunohistochemical staining. FOXA3 transcription is specifically induced by XBP1s upon ER stress. FOXA3 exacerbates the excessive lipid accumulation caused by the acute ER-inducer TM, whereas FOXA3 deficiency in hepatocytes and mice alleviates it. Importantly, FOXA3 deficiency in mice reduced diet-induced chronic ER stress, fatty liver, and insulin resistance. In addition, FOXA3 suppression via siRNA or adeno-associated virus delivery ameliorated the fatty liver phenotype in HFD-fed and db/db mice. Mechanistically, ChIP-Seq analysis revealed that FOXA3 directly regulates Period1 (Per1) transcription, which in turn promotes the expression of lipogenic genes, including Srebp1c, thus enhancing lipid synthesis. Of pathophysiological significance, FOXA3, PER1, and SREBP1c levels were increased in livers of obese mice and patients with NAFLD. The present study identified FOXA3 as the bridging molecule that links ER stress and NAFLD progression. Our results highlighted the role of the XBP1s-FOXA3-PER1/Srebp1c transcriptional axis in the development of NAFLD and identified FOXA3 as a potential therapeutic target for fatty liver disease. The molecular mechanisms linking endoplasmic reticulum stress to non-alcoholic fatty liver disease (NAFLD) progression remain undefined. Herein, via invitro and invivo analysis, we identified Forkhead box A3 (FOXA3) as a key bridging molecule. Of pathophysiological significance, FOXA3 protein levels were increased in livers of obese mice and patients with NAFLD, indicating that FOXA3 could be a potential therapeutic target in fatty liver disease.

Effects of earthworm extract on the lipid profile and fatty liver induced by a high-fat diet in guinea pigs.

BackgroundNon-alcoholic fatty liver disease (NAFLD), characterized by the accumulation of excess fat in the liver in people who consume little or no alcohol, is becoming increasingly common around the world, especially in developed countries. Extracts from earthworms have been used as alternative therapies for a variety of diseases but not in NAFLD. Therefore, the aim of this study was to investigate the effect of earthworm extract (EE) on diet-induced fatty liver disease in guinea pigs.MethodsEE was extracted, and the effect of EE on the lipid levels and liver damage in guinea pigs fed a high-fat diet (HFD) was assessed. Thirty male guinea pigs at 3 weeks of age were allocated equally to five groups, namely, chow diet, HFD, and HFD with different dosages (0.3, 1.4 and 6.8 µg per kg bodyweight per day) of EE for 4 weeks, and their body weight was monitored throughout the experiment. Liver tissues were examined for gross morphology and histology. Serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), alanine transaminase (ALT) and aspartate aminotransferase (AST) were determined using an autoanalyser.ResultsHFD induced NAFLD in guinea pigs. HFD-fed guinea pigs that received EE treatment showed milder increases in the serum levels of TC, TG and LDL-C, as well as in the body weight growth rate, compared to the HFD group without EE supplementation. EE intervention reduced the number of lipid-containing hepatocytes, hepatocellular ballooning and sinusoidal distortion in the liver in HFD-fed animals. ALT in serum was significantly elevated by HFD. No statistically significant difference in ALT levels was found between the chow diet group and the HFD group with EE treatment.ConclusionsThis study demonstrates that the administration of EE suppressed the induction of serum TC, TG and LDL-C in response to HFD. EE also reduced liver damage in HFD-fed guinea pigs. These findings suggest that EE has alleviating effects on dyslipidaemia and liver damage associated with NAFLD.

High-Fat Diet-Induced Fatty Liver Is Associated with Immunosuppressive Response during Sepsis in Mice.

High-fat diet-induced fatty liver is an indolent and chronic disease accompanied by immune dysfunction and metabolic disturbances involving numerous biological pathways. This study investigated how this abnormal metabolic disorder influences sepsis in mice. Mice were fed with normal chow (NC) or high-fat diet (HFD), and palmitic acid (PA) was used to treat hepatocytes to mimic fat accumulation in vitro. Lipopolysaccharide (LPS) was used to induce sepsis and related immune responses. Mice fed on a high-fat diet displayed higher mortality and more severe liver damage but compromised immunoreaction. The supernatant from PA-treated primary hepatocytes markedly diminished the inflammatory cytokine expression of macrophages after LPS stimulation, which showed a state of immunosuppression. Metabolomics analysis indicated the level of many key metabolites with possible roles in immunoreaction was altered in the HFD and PA groups compared with corresponding controls; specifically, β-hydroxybutyric acid (BHB) showed an immunosuppressive effect on Raw264.7 cells during the LPS stimulation. Transcriptomic analysis suggested that several differential signaling pathways may be associated with the alteration of immune function between the NC and HFD groups, as well as in the in vitro model. Our study suggests that the consumption of HFD may alter the hepatic metabolic profile, and that certain metabolites may remold the immune system to immunosuppressive state in the context of sepsis.

Beneficial effects of Lactobacillus-fermented black barley on high fat diet-induced fatty liver in rats.

A long-term high-fat (HF) diet can cause metabolic disorders, which might induce visceral obesity and ectopic triglyceride storage (e.g., hepatic steatosis), and increase hepatic oxidative stress. Oxidative stress plays a significant role in the development of complications associated with obesity. Fermented whole cereal foods exhibit healthy potential due to their unique phytochemical composition and the presence of probiotics. In the present study, the regular nutrients and phytochemicals of Lactobacillus-fermented black barley (Hordeum distichum L.) were analyzed. Further, the black barley fermentation broth (1 mL per 100 g BW per d, equivalent to 1 mL per kg BW of daily human intake) was administered orally to the rats fed on a high fat diet (HF). The anti-oxidative activity and hepatic metabolic profile of Lactobacillus-fermented black barley were investigated. The results showed that the fermentation processing significantly increased the contents of polyphenols (e.g., ferulic acid, etc.), flavonoids (e.g., flavone, etc.), vitamin B1 and B2, partial mineral elements (e.g., Ca, etc.), and thymine. Furthermore, compared to the HF-fed only rats, fermented black barley treatment significantly increased the activities of SOD (superoxide dismutase) and GSH-PX (glutathione peroxidase), and decreased the level of TBARS (thiobarbituric acid reactive substances) in serum, the levels of TG (triglyceride), TC (total cholesterol), NEFA (non-esterified fatty acid) in the liver, and the levels of TC, NEFA in the adipose tissue. This suggested the beneficial effects of fermented black barley on ameliorating oxidative stress and hepatic steatosis, which could be attributed to its regulatory role in the hepatic metabolism of glycerophospholipids, nicotinate and nicotinamide, glutathione, and nucleotide, and on the expression of genes related to oxidative stress (Heat shock protein 90 and reactive oxygen species modulator 1).

Effects of Dietary Supplementation with Myo-inositol on Hepatic Expression of Glycolytic and Fructolytic Enzyme Genes in Rats Fed a High-sucrose Diet.

We examined effects of a major lipotrope, myo-inositol, on the expression of primary glycolytic (glucokinase and phosphofructokinase) and fructolytic enzyme (ketohexokinase [KHK] and aldolase B) genes in the livers of rats fed a control diet, high-sucrose diet, or high-sucrose diet supplemented with 0.5% myo-inositol for 14 d. Supplementation with myo-inositol decreased the hepatic expression of fructolytic enzyme genes, but not that of glycolytic enzyme genes, and the levels of triglycerides, fatty acid synthase, and KHK proteins in high-sucrose diet-induced fatty liver. The study results suggest that myo-inositol represses primary fructlysis, but not glycolysis, in high-sucrose diet-induced fatty liver.

Dietary supplementation with myo-inositol reduces high-fructose diet-induced hepatic ChREBP binding and acetylation of histones H3 and H4 on the Elovl6 gene in rats

ELOVL fatty acid elongase 6 (ELOVL6) is a long-chain fatty acid elongase, and the hepatic expression of the Elovl6 gene and accumulation of triglycerides (TG) are enhanced by long-term high-fructose intake. Fatty acid synthesis genes, including Elovl6, are regulated by lipogenic transcription factors, sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP). In addition, carbohydrate signals induce the expression of fatty acid synthase not only via these transcription factors but also via histone acetylation. Since a major lipotrope, myo-inositol (MI), can repress short-term high-fructose-induced fatty liver and the expression of fatty acid synthesis genes, we hypothesized that MI might influence SREBP-1c, ChREBP, and histone acetylation of Elovl6 in fatty liver induced by even short-term high-fructose intake. This study aimed to investigate whether dietary supplementation with MI affects Elovl6 expression, SREBP-1 and ChREBP binding, and acetylation of histones H3 and H4 at the Elovl6 promoter in short-term high-fructose diet-induced fatty liver in rats. Rats were fed a control diet, high-fructose diet, or high-fructose diet supplemented with 0.5% MI for 10 days. This study showed that MI supplementation reduced short-term high-fructose diet-induced hepatic expression of the Elovl6 gene, ChREBP binding, but not SREBP-1 binding, and acetylation of histones H3 and H4 at the Elovl6 promoter.

Hepatoprotective and anti-inflammatory effects of a standardized pomegranate (Punica granatum) fruit extract in high fat diet-induced obese C57BL/6 mice

Diets rich in fats are linked to elevated systemic inflammation, which augments the progression of inflammatory-related disorders including non-alcoholic fatty liver disease (NAFLD) and neurodegenerative diseases. A phenolic-enriched pomegranate fruit extract (PE) was investigated for its hepatoprotective and anti-inflammatory effects in male C57BL/6 mice fed either a high-fat diet or a standard rodent diet with or without 1% of PE for 12 weeks. Mouse livers and hippocampi were evaluated for the expression of genes associated with NAFLD and inflammation by multiplexed gene analysis. PE alleviated diet-induced fatty liver and suppressed hepatic lipid regulating genes including Cd36, Fas, Acot2 and Slc27a1. In addition, PE suppressed gene expression of pro-inflammatory cytokines including Il-1α, Il-7, Il-11, Ifnα, Tnfα and Lepr in the hippocampi. Our findings support the protective effects of PE against high-fat diet-induced hepatic and neurological disease.

Autophagy and liver cancer.

Autophagy is a highly conserved catabolic process that degrades cytosolic proteins and organelles via formation of autophagosomes that fuse with lysosomes to form autolysosomes, whereby autophagic cargos are degraded. Numerous studies have demonstrated that autophagy plays a critical role in the regulation of liver physiology and homeostasis, and impaired autophagy leads to the pathogenesis of various liver diseases such as viral hepatitis, alcohol associated liver diseases (AALD), non-alcoholic fatty liver diseases (NAFLD), and liver cancer. Recent evidence indicates that autophagy may play a dual role in liver cancer: inhibiting early tumor initiation while promoting progression and malignancy of already formed liver tumors. In this review, we summarized the progress of current understanding of how hepatic viral infection, alcohol consumption and diet-induced fatty liver diseases impair hepatic autophagy. We also discussed how impaired autophagy promotes liver tumorigenesis, and paradoxically how autophagy is required to promote the malignancy and progression of liver cancer. Understanding the molecular mechanisms underlying how autophagy differentially affects liver cancer development and progression may help to design better therapeutic strategies for prevention and treatment of liver cancer.

Dyrk1b Displaces Fkbp12 from mTORC2, Causes its Activation and Triggers De Novo Lipogenesis: Implications for the Treatment of Diet-Induced Fatty Liver Disease

The mechanisms that unify the association of insulin-induced de novo lipogenesis (DNL) with hepatic insulin resistance in metabolic syndrome (MetS) are not understood. We had previously shown that rare mutations in the DYRK1B gene are associated with MetS. We now demonstrate that Dyrk1b is a missing link between DNL and hepatic insulin resistance. The increased levels of liver Dyrk1b promoted, while its disruption conferred protection against enhanced glucose production, liver insulin-resistance and steatosis in mice. Mechanistically, Dyrk1b facilitated insulin-induced DNL in a kinase-independent manner by displacing Fkbp12 from mTORC2, causing its activation. Accordingly, the disruption of the hepatic mTORC2 rescued Dyrk1b induced hepatic steatosis and hyperlipidemia. The significance of this disease pathway is further illustrated by increased hepatic Dyrk1b levels in mice and humans with hepatic steatosis. These findings identify Dyrk1b and Fkbp12 as regulators of DNL in the setting of hepatic insulin resistance and attractive therapeutic targets against metabolic syndrome.

Erica multiflora extract rich in quercetin-3-O-glucoside and kaempferol-3-O-glucoside alleviates high fat and fructose diet-induced fatty liver disease by modulating metabolic and inflammatory pathways in Wistar rats

The wide morbidity of obesity has heightened interest in providing natural and safe compounds to maintain optimal health. The present study was designed to determine the chemical constituents and the effects of methanol leaf extract from Erica multiflora (M-EML) on mitigating high-fat and high-fructose diet (HFFD)-induced metabolic syndrome (MS).LC–MS/MS characterization of M-EML allowed the identification of 14 secondary metabolites and showed that quercetin-3-O-glucoside and kaempferol-3-O-glucoside were the main compounds of our extract. In the in vivo study, the oral administration of M-EML (250 mg/kg) during the last 4 weeks of the experimentation alleviated HFFD-induced obesity, insulin resistance (IR) and cardiovascular diseases. Thus, M-EML treatment significantly normalized body and liver weight, allowed to a sharp decline in plasma levels of TC, TG and LDL-c by 32%, 35% and 66%, respectively. Moreover, hepatic enzymes, total and direct bilirubin, lipase and uric acid levels have been diminished in treated group. Histopathology of the liver confirmed the changes induced by HFFD and the hepatoprotective effect of M-EML. The supply of M-EML reduced NO production and cellular lysosomal enzyme activity by 44% and 60%, respectively compared to HFFD. Besides, M-EML showed decreased pro-inflammatory cytokines levels (259.5±47.35 pg/ml and 56.08±1.56 pg/ml) of TNF-α and IL-6, respectively.In addition, M-EML reduced liver malondialdehyde (MDA) content and enhanced superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities. In contrast, these enzymatic activities have been disrupted in HFFD rats.Overall, M-EML prevented obesity through the modulation of metabolic syndrome, reducing inflammation and promoting antioxidant enzymes activities.

Low-arginine and low-protein diets induce hepatic lipid accumulation through different mechanisms in growing rats

BackgroundDietary protein deficiency and amino acid imbalance cause hepatic fat accumulation. We previously demonstrated that only arginine deficiency or total amino acid deficiency in a diet caused significant hepatic triglyceride (TG) accumulation in young Wistar rats. In this study, we explored the mechanisms of fatty liver formation in these models.MethodsWe fed 6-week-old male Wistar rats a control diet (containing an amino acid mixture equivalent to 15% protein), a low-total-amino acid diet (equivalent to 5% protein; 5PAA), and a low-arginine diet (only the arginine content is as low as that of the 5PAA diet) for 2 weeks.ResultsMuch greater hepatic TG accumulation was observed in the low-arginine group than in the low-total-amino acid group. The lipid consumption rate and fatty acid uptake in the liver did not significantly differ between the groups. In contrast, the low-total-amino acid diet potentiated insulin sensitivity and related signaling in the liver and enhanced de novo lipogenesis. The low-arginine diet also inhibited hepatic very-low-density lipoprotein secretion without affecting hepatic insulin signaling and lipogenesis.ConclusionsAlthough the arginine content of the low-arginine diet was as low as that of the low-total-amino acid diet, the two diets caused fatty liver via completely different mechanisms. Enhanced lipogenesis was the primary cause of a low-protein diet-induced fatty liver, whereas lower very-low-density lipoprotein secretion caused low-arginine diet-induced fatty liver.

Artemisia annua extract ameliorates high-fat diet-induced fatty liver by activating AMPK

Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common liver disease in industrialized countries. Recently, natural compounds that may be beneficial for improving NAFLD have received increasing attention. Artemisia annua L. is the source of antimalarial phytomolecule, artemisinin, which has been reported to prevent obesity. However, the effect of A. annua extract on hepatic lipid metabolism remains unclear. This study was performed to determine the protective effect of Artemisia annua extract (AAE) on high-fat diet (HFD)-induced hepatic lipid accumulation, and elucidate the molecular mechanisms behind its effects in vivo and in vitro. We found that HFD-fed mice with AAE administration (50 mg/kg/day) for 8 weeks dramatically reduced hepatic lipid accumulation compared to the control mice taken with HFD alone. The body and liver weights of AAE group were significantly lower than those of HFD group, and oral administration of AAE remarkably suppressed the serum levels of triglyceride (TG), total cholesterol (TC), fasting glucose, alanine transaminase (ALT) and aspartate transaminase (AST) in HFD-fed mice. AAE significantly increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in the liver of HFD-fed mice and HepG2 hepatocytes. Moreover, AAE downregulated the hepatic expression of sterol regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) in HFD-fed mice and high glucose-treated HepG2 cells. In addition, the inhibitory effects of AAE on the overexpression of SREBP-1c and FAS were attenuated by compound C, which is the specific AMPK inhibitor, in high glucose-treated HepG2 cells. These results indicated that AAE may represent a promising approach for the prevention and treatment of obesity-related NAFLD via the activation of AMPK and the regulation of AMPK-dependent lipogenic genes.

Hempseed (Cannabis sativa) lipid fractions alleviate high-fat diet-induced fatty liver disease through regulation of inflammation and oxidative stress

Diet and lifestyle-induced dysregulated lipid metabolism have been implicated in fatty liver disease. Chronic redox modulation and hepatic inflammation are key pathological mediators and hallmarks of fatty liver disease associated liver steatosis and steatohepatitis. In this context, owing to the beneficial phytochemical properties such as optimal omega-6: omega-3 PUFA ratio of hempseed, we aimed to explore its potential anti-inflammatory and antioxidant properties against high-fat diet (HFD)-induced experimental model of fatty liver disease. The hempseed lipid fractions (HEMP) were prepared and their ameliorating effects on HFD induced morphological changes, lipid profiles, liver function markers (LFT), markers of oxidative stress and inflammation were studied. Results indicated that HEMP administration to hypercholesterolemic rats resolved the morphological, histopathological, and biochemical indicators of fatty liver diseases. Further, the mechanistic evidence revealed that these hepatoprotective effects of HEMP are mediated through inhibition of oxidative stress and inflammatory mediators such as Cox-2, hPGDS, mPGES, IL-4, TNF-α and sEH. In conclusion, current study suggests the plausible antioxidant and anti-inflammatory role of HEMP in alleviating pathophysiological conditions including fatty liver disease, where oxidative stress and inflammation are key mediators.

1957-P: Intermittent Ketogenic Diet Ameliorates Diet-Induced Obesity and Fatty Liver with Improved FGF21 Signaling

Recently, ketogenic diet has been found to be effective on improving obesity. Fibroblast growth factor 21 (FGF-21) is an endocrine factor mainly synthesized in the liver and shown to impact the metabolism of multiple tissues. Here, we investigated the effect of intermittent ketogenic diet on obesity and the sensitivity of FGF-21. Eight-week-old C57BL/6 mice were subjected to a chow diet (CD group), a high fat diet (HFD group), an intermittent chow diet (iCD group) or an intermittent ketogenic diet (iKD group) for 16 weeks. The intermittent diet intervention began with an HFD and was alternated with a chow diet or a ketogenic diet biweekly. Although the average energy intake of iKD group was highest in the four groups, the body weight, fasting blood glucose, the body fat mass and the weight of liver, epididymal adipose tissues (eWAT), subcutaneous adipose tissue (sWAT) and brown adipose tissue (BAT) of iKD group were ameliorated remarkably when compared to HFD group. The insulin sensitivity of iKD group was greatly improved as well. Both the histological results and the quantification of liver triglyceride showed that hepatic steatosis was significantly alleviated in iKD group. Western blotting showed that lipid metabolism in liver was greatly improved by iKD. What’s more, the cold exposure test showed that the iKD group had the best cold tolerance in the four groups. The mRNA expression of FGF-21 was greatly upregulated and hepatic inflammation was ameliorated in livers of iKD group. HE staining showed that the adipocytes in eWAT and sWAT were smaller in iKD group. The whitening of BAT was also improved in iKD group. Both mRNA and protein levels of UCP1 and PGC1α were remarkably upregulated by iKD in eWAT, sWAT and BAT. The mRNA levels of FGFR1 and KLB, which are related to FGF-21 sensitivity, were observed to be improved in eWAT and sWAT. Our data demonstrated that iKD ameliorates diet-induced obesity and fatty liver, and improved insulin sensitivity and cold tolerance with improved FGF-21 signaling. Disclosure W. Guo: None. W. Wang: None. W. Li: None.