Gut-liver axis modulation of Panax notoginseng saponins in nonalcoholic fatty liver disease

Abstract Background and aims Nonalcoholic fatty liver disease (NAFLD) is an obesity-related comorbidity, and it is characterized as a spectrum of liver abnormalities, including inflammation, steatosis, and fibrosis. The gut-liver axis is implicated in the pathogenesis and development of NAFLD. A promising drug agent targeting the gut-liver axis is expected to reverse NAFLD. Methods We utilized high-fat diet (HFD)-induced obese mice and obesity-prone Lepob mice to examine the gut-liver regulation of the natural medicine Panax Notoginseng Saponins (PNS) on NAFLD. Results PNS exhibited potent anti-lipogenesis and anti-fibrotic effects in NAFLD mice, that was associated with the TLR4-induced inflammatory signalling pathway in liver. More strikingly, PNS treatment caused a deceleration of gut-to-liver translocation of microbiota-derived short chain fatty acids (SCFAs) products. PNS-induced TLR4 inhibition and restoration of Claudin-1 and ZO-1 proteins in the gut-liver axis contributed to the reverse of leaky gut, which in turn abolished by the addition of lipopolysaccharide (LPS), an agonist of TLR4. Specifically, hepatic steatosis in HFD-treated mice was attenuated by PNS through regulating AMPKα, but restored by the replenishment of LPS. Meanwhile, the anti-fibrotic effect of PNS was abolished by LPS stimulation via the overproduction of collagen I/IV and α-SMA. Conclusion PNS exerted hepatoprotection against NAFLD in both ob/ob and HFD-induced obese mice, primarily by mediating the gut-liver axis in a TLR4-dependent manner. Graphic abstract

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Dietary fiber‐derived short‐chain fatty acids: A potential therapeutic target to alleviate obesity‐related nonalcoholic fatty liver disease

Obesity Reviews ◽

10.1111/obr.13316 ◽

2021 ◽

Author(s):

Shumin Zhang ◽

Jingwen Zhao ◽

Fei Xie ◽

Hengxun He ◽

Lee J. Johnston ◽

...

Keyword(s):

Fatty Acids ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Dietary Fiber ◽

Therapeutic Target ◽

Fatty Liver Disease ◽

Short Chain Fatty Acids ◽

Potential Therapeutic Target ◽

Nonalcoholic Fatty Liver

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Psoralea corylifolia L. Seed Extract Attenuates Nonalcoholic Fatty Liver Disease in High-Fat Diet-Induced Obese Mice

Nutrients ◽

10.3390/nu8020083 ◽

2016 ◽

Vol 8 (2) ◽

pp. 83 ◽

Cited By ~ 12

Author(s):

Eunhui Seo ◽

Yoon Sin Oh ◽

Hee-Sook Jun

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Seed Extract ◽

Obese Mice ◽

Psoralea Corylifolia ◽

High Fat ◽

Nonalcoholic Fatty Liver

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Disease-specific eQTL screening reveals an anti-fibrotic effect of AGXT2 in nonalcoholic fatty liver disease

10.1101/2021.03.22.436368 ◽

2021 ◽

Author(s):

Taekyeong Yoo ◽

Sae Kyung Joo ◽

Hyo Jung Kim ◽

Hyun Young Kim ◽

Hyungtai Sim ◽

...

Keyword(s):

Liver Disease ◽

Liver Fibrosis ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Genetic Factors ◽

Dependent Manner ◽

Nonalcoholic Fatty Liver ◽

Causal Genes ◽

Disease Specific

AbstractBackground & AimsNonalcoholic fatty liver disease (NAFLD) poses an impending clinical burden. Genome-wide association studies have revealed a limited contribution of genomic variants to the disease, requiring alternative but robust approaches to identify disease-associated variants and genes. We carried out a disease-specific expression quantitative trait loci (eQTL) screen to identify novel genetic factors that specifically act on NAFLD progression on the basis of genotype.MethodsWe recruited 125 Korean biopsy-proven NAFLD patients and healthy individuals and performed eQTL analyses using 21,272 transcripts and 3,234,941 genotyped and imputed SNPs. We then selected eQTLs that were detected only in the NAFLD group, but not in the control group (i.e., NAFLD-eQTLs). An additional cohort of 162 Korean NAFLD individuals was used for replication. The function of the selected eQTL toward NAFLD development was validated using HepG2, primary hepatocytes and NAFLD mouse models.ResultsThe NAFLD-specific eQTL screening yielded 242 loci. Among them, AGXT2, encoding alanine-glyoxylate aminotransferase 2, displayed decreased expression in NAFLD patients homozygous for the non-reference allele of rs2291702, compared to no-NAFLD subjects with the same genotype (P = 4.79 × 10−6). This change was replicated in an additional 162 individuals, yielding a combined P-value of 8.05 × 10−8 from a total of 245 NAFLD patients and 48 controls.Knockdown of AGXT2 induced palmitate-overloaded hepatocyte death by increasing ER stress, and exacerbated NAFLD diet-induced liver fibrosis in mice. However, overexpression of AGXT2 reversely attenuated liver fibrosis and steatosis as well.ConclusionsWe implicate a new molecular role of AGXT2 in NAFLD. Our overall approach will serve as an efficient tool for uncovering novel genetic factors that contribute to liver steatosis and fibrosis in patients with NAFLD.Lay summaryElucidating causal genes for NAFLD has been challenging due to limited tissue availability and the polygenic nature of the disease. Using liver and blood samples from 125 biopsy-proven NAFLD and no-NAFLD Korean individuals and an additional 162 individuals for replication, we devised a new analytic method to identify causal genes. Among the candidates, we found that AGXT2-rs2291702 protects against liver fibrosis in a genotype-dependent manner with the potential for therapeutic interventions. Our approach enables the discovery of NAFLD causal genes that act on the basis of genotype.

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Impact of SchisandraChinensis Bee Pollen on Nonalcoholic Fatty Liver Disease and Gut Microbiota in HighFat Diet Induced Obese Mice

Nutrients ◽

10.3390/nu11020346 ◽

2019 ◽

Vol 11 (2) ◽

pp. 346 ◽

Cited By ~ 4

Author(s):

Ni Cheng ◽

Sinan Chen ◽

Xinyan Liu ◽

Haoan Zhao ◽

Wei Cao

Keyword(s):

Liver Disease ◽

Phenolic Compounds ◽

Gut Microbiota ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Total Phenolic ◽

Human Beings ◽

Obese Mice ◽

Nonalcoholic Fatty Liver

Schisandrachinensisbee pollen has been used as a health food in China for centuries; however, its bioactive constituents and functions are not very clear. In this study, we investigated the phenolic compounds of Schisandrachinensisbee pollen extract (SCPE) by UHPLC-Q-Orbitrap-HRMS/HPLC-DAD-ECD and its prevention from nonalcoholic fatty liver disease (NAFLD) and modulation of gut microbiota in high fat diet induced obese C57BL/6 mice. The results showed that 12 phenolic compounds were identified in SCPE, and naringenin, rutin and chrysin were the main constituents. The content of naringenin reached 1.89 mg/g, and total phenolic content (TPC) of SCPE were 101.83 mg GA/g. After obese mice were administrated with SCPE at 7.86 and 15.72 g/kg BW for 8 weeks, body weight gains were reduced by 18.23% and 19.37%. SCPE could decrease fasting blood glucose, cut down the lipid accumulation in serum and liver, lessen oxidative injury and inflammation in obesity mice. Moreover, SCPE could effectively inhibit the formation of NAFLD by inhibition of LXR-α, SREBP-1c and FAS genes expression, and modulate the structural alteration of gut microbiota in obesity mice. These findings suggested that SCPE could attenuate the features of the metabolism syndrome in obesity mice, which can be used to prevent obesity and NAFLD of human beings.

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Curcumin Improved Glucose Intolerance, Renal Injury, and Nonalcoholic Fatty Liver Disease and Decreased Chromium Loss through Urine in Obese Mice

Processes ◽

10.3390/pr9071132 ◽

2021 ◽

Vol 9 (7) ◽

pp. 1132

Author(s):

Geng-Ruei Chang ◽

Wen-Tsong Hsieh ◽

Lan-Szu Chou ◽

Chen-Si Lin ◽

Ching-Fen Wu ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Glucose Intolerance ◽

Renal Injury ◽

Fatty Liver Disease ◽

Renal Damage ◽

Control Group ◽

Obese Mice ◽

Nonalcoholic Fatty Liver

Obesity-associated hyperglycemia underlies insulin resistance, glucose intolerance, and related metabolic disorders including type 2 diabetes, renal damage, and nonalcoholic fatty liver disease. Turmeric root is commonly used in Asia, and curcumin, one of its pharmacological components, can play a role in preventing and treating certain chronic physiological disorders. Accordingly, this study examined how high-fat diet (HFD)-induced hyperglycemia and hyperlipidemia are reduced by curcumin through changes in fatty liver scores, chromium distribution, and renal injury in mice. Relative to the control group, also fed an HFD, the curcumin group weighed less and had smaller adipocytes; it also had lower daily food efficiency, blood urea nitrogen and creatinine levels, serum alanine aminotransferase and aspartate aminotransferase levels, serum and hepatic triglyceride levels, and hepatic lipid regulation marker expression. The curcumin-treated obese group exhibited significantly lower fasting blood glucose, was less glucose intolerant, had higher Akt phosphorylation and glucose transporter 4 (GLUT4) expression, and had greater serum insulin levels. Moreover, the group showed renal damage with lower TNF-α expression along with more numerous renal antioxidative enzymes that included superoxide dismutase, glutathione peroxidase, and catalase. The liver histology of the curcumin-treated obese mice showed superior lipid infiltration and fewer FASN and PNPLA3 proteins in comparison with the control mice. Curcumin contributed to creating a positive chromium balance by decreasing the amount of chromium lost through urine, leading to the chromium mobilization needed to mitigate hyperglycemia. Thus, the results suggest that curcumin prevents HFD-induced glucose intolerance, kidney injury, and nonalcoholic fatty liver disease.

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Hepatic p38 activation modulates systemic metabolism through FGF21-mediated interorgan communication

10.2337/figshare.16811332.v1 ◽

2021 ◽

Author(s):

Wei Liu ◽

Chao Sun ◽

Ying Yan ◽

Hongchao Cao ◽

Zhoumin Niu ◽

...

Keyword(s):

Insulin Resistance ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Liver Steatosis ◽

Dependent Manner ◽

Peripheral Tissues ◽

Nonalcoholic Fatty Liver ◽

Protein Levels

The mechanisms underlying the pathogenesis of steatosis and insulin resistance in nonalcoholic fatty liver disease remain elusive. Increased phosphorylation of hepatic p38 has long been noticed in fatty liver; however, whether the activation of hepatic p38 is a cause or consequence of liver steatosis is unclear. Here, we demonstrate that hepatic p38 activation by MKK6 overexpression in the liver of mice induces severe liver steatosis, reduces fat mass, and elevates circulating fatty acid levels in a hepatic p38a- and FGF21-dependent manner. Mechanistically, through increasing the FGF21 production from liver, hepatic p38 activation increases the influx of fatty acids from adipose tissue to liver, leading to hepatic ectopic lipid accumulation and insulin resistance. Although hepatic p38 activation exhibits favorable effects in peripheral tissues, it impairs the hepatic FGF21 action by facilitating the ubiquitination and degradation of FGF21 receptor cofactor b-Klotho. Consistently, we show that p38 phosphorylation and FGF21 expression are increased, b-Klotho protein levels are decreased in the fatty liver of either mice or patients. In conclusion, our study reveals previously undescribed effects of hepatic p38 activation on systemic metabolism and provides new insights into the roles of hepatic p38a, FGF21, and b-Klotho in the pathogenesis of nonalcoholic fatty liver disease.

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