Loss of hepatic Lgr4 and Lgr5 promotes nonalcoholic fatty liver disease

Background & Aims: The Rspo–Lgr4/5–Znrf3/Rnf43 module is a master regulator of hepatic Wnt/β–catenin signaling and metabolic zonation, but its impact on nonalcoholic fatty liver disease (NAFLD) remains unclear. We studied whether liver–specific loss of the Wnt/β–catenin modulators Leucine–Rich Repeat–Containing G Protein–Coupled Receptor 4/5 (Lgr4/5) promotes nonalcoholic fatty liver disease (NAFLD). Methods: Mice with liver–specific deletion of both receptors Lgr4/5 (Lgr4/5dLKO) were fed with normal diet (ND) or high fat diet (HFD). Livers of these mice were analyzed for lipid and fibrotic content by tissue staining and immunohistochemistry (IHC), and lipoproteins, inflammation and liver enzyme markers were measured in blood. Mechanistic insights into hepatic lipid accumulation were obtained by using ex vivo primary hepatocyte cultures derived from the Lgr4/5dLKO mice. Lipid analysis of mouse livers was performed by mass spectrometry (MS)–based untargeted lipidomic analysis. Results: We demonstrated that liver-specific ablation of Lgr4/5–mediated Wnt signaling resulted in hepatic steatosis, impaired bile acid (BA) secretion and predisposition to liver fibrosis. Under HFD conditions, we observed progressive intrahepatic fat accumulation, developing into macro–vesicular steatosis. Serum lipoprotein levels in HFD–fed Lgr4/5dLKO mice were decreased, rather than increased, suggesting that accumulation of fat in the liver was due to impaired lipid secretion by hepatocytes. Our lipidome analysis revealed a severe alteration of several lipid species in livers of Lgr4/5dLKO mice, including triacylglycerol estolides (TG–EST), a storage form of bioactive free fatty acid (FA) esters of hydroxy FAs (FAHFAs). Conclusions: Loss of hepatic Wnt/β–catenin activity by Lgr4/5 deletion led to deregulation of lipoprotein pathways, loss of BA secretion, intrinsic alterations of lipid homeostasis and the onset of NAFLD.

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Acupuncture on ST36, CV4 and KI1 Suppresses the Progression of Methionine- and Choline-Deficient Diet-Induced Nonalcoholic Fatty Liver Disease in Mice

Metabolites ◽

10.3390/metabo9120299 ◽

2019 ◽

Vol 9 (12) ◽

pp. 299 ◽

Cited By ~ 4

Author(s):

Xiangjin Meng ◽

Xin Guo ◽

Jing Zhang ◽

Junji Moriya ◽

Junji Kobayashi ◽

...

Keyword(s):

Lipid Metabolism ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Acupuncture Treatment ◽

Lipid Analysis ◽

Altered Expression ◽

Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, and its treatment remain a constant challenge. A number of clinical trials have shown that acupuncture treatment has beneficial effects for patients with NAFLD, but the molecular mechanisms underlying its action are still largely unknown. In this study, we established a mouse model of NAFLD by administering a methionine- and choline-deficient (MCD) diet and selected three acupoints (ST36, CV4, and KI1) or nonacupoints (sham) for needling. We then investigated the effects of acupuncture treatment on the progression of NAFLD and the underlying mechanisms. After two weeks of acupuncture treatment, the liver in the needling-nonapcupoint group (NG) mice appeared pale and yellowish in color, while that in the needling-acupoint group (AG) showed a bright red color. Histologically, fewer lipid droplets and inflammatory foci were observed in the AG liver than in the NG liver. Furthermore, the expression of proinflammatory signaling factors was significantly downregulated in the AG liver. A lipid analysis showed that the levels of triglyceride (TG) and free fatty acid (FFA) were lower in the AG liver than in the NG liver, with an altered expression of lipid metabolism-related factors as well. Moreover, the numbers of 8-hydroxy-2′-deoxyguanosine (8-OHdG)-positive hepatocytes and levels of hepatic thiobarbituric acid reactive substances (TBARS) were significantly lower in AG mice than in NG mice. In line with these results, a higher expressions of antioxidant factors was found in the AG liver than in the NG liver. Our results indicate that acupuncture repressed the progression of NAFLD by inhibiting inflammatory reactions, reducing oxidative stress, and promoting lipid metabolism of hepatocytes, suggesting that this approach might be an important complementary treatment for NAFLD.

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Hepatoprotective Effects of a Novel Trihoney against Nonalcoholic Fatty Liver Disease: A Comparative Study with Atorvastatin

The Scientific World JOURNAL ◽

10.1155/2020/4503253 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Hamad Abdulsalam Hamad Alfarisi ◽

Muhammad Bin Ibrahim ◽

Zenab B. Hamad Mohamed ◽

Nuraniza Azahari ◽

Asmah Hanim Bt. Hamdan ◽

...

Keyword(s):

Liver Disease ◽

Liver Function ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Normal Diet ◽

Cholesterol Diet ◽

Nonalcoholic Fatty Liver ◽

Hepatoprotective Effects ◽

Glutamyl Transferase

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder worldwide with no curative therapy. The aim of this study was to investigate the hepatoprotective effects of a novel Trihoney against biochemical and histological manifestations of NAFLD in hypercholesterolemic rabbits. Methodology. Forty-eight male New Zealand white (NZW) rabbits were grouped into normal diet (C), normal diet with 0.6 g/kg/day of Trihoney (C + H), 1% cholesterol diet (HCD), 1% cholesterol diet with 0.3 g/kg/day of Trihoney (HCD + H1), 1% cholesterol diet with 0.6 g/kg/day of Trihoney (HCD + H2), and 1% cholesterol diet with 2 mg/kg/day of atorvastatin (HCD + At.). Animals were sacrificed after 12 weeks of treatment. Serum lipids and liver function test (LFT) were measured prior to and at the endpoint of the experiment for total cholesterol (TC), low-density lipoprotein (LDL-c), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin (T. Bil.). Liver was processed for histopathology study. Liver homogenate was analysed for oxidative stress parameters: superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA). Results. Lipid analysis approved the induction of hypercholesterolemia. A significant elevation (p<0.01) of serum AST and ALT levels showed by the HCD group was compared to C and C + H groups. Trihoney exhibited a significant reduction (p<0.001) of AST and ALT compared to the HCD group. Likewise, AST and ALT reduced significantly in the HCD + At. group (p<0.001). Trihoney supplementation induced significant (p<0.05) enhancement of SOD and GPx activities. Atorvastatin treatment was associated with significant (p<0.05) reduction of SOD and GPx activities in the liver. Trihoney and atorvastatin showed marked (p<0.001) reduction of hepatic lipid peroxidation. Trihoney showed histological protection against progression of NAFLD to nonalcoholic steatohepatitis (NASH). Atorvastatin exhibited no beneficial impact on hepatic architecture. Conclusion. Trihoney was able to maintain normal liver function and showed hepatoprotection against progression of NAFLD to NASH probably through hypocholesterolaemic and antioxidant functions.

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Feasibility of a Novel Nonhuman Primate Model of Age-Related Nonalcoholic Fatty Liver Disease

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.584 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A287-A288

Author(s):

Parveez Ahamed Abdul Azees ◽

Juan Pablo Palavicini ◽

Xianlin Han ◽

Adam Salmon ◽

Amrita Kamat

Keyword(s):

Cardiovascular Disease ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Hepatic Steatosis ◽

Fatty Liver Disease ◽

Nonalcoholic Fatty Liver ◽

Triglyceride Accumulation ◽

Age Related ◽

Lipid Species

Abstract The objective of the proposed study is to investigate the feasibility of the marmoset as an animal model to study age-associated nonalcoholic fatty liver disease (NAFLD). This chronic liver disease includes a spectrum of disorders ranging from increased triglyceride accumulation in the liver or hepatic steatosis to the more severe inflammatory form nonalcoholic steatohepatitis that can lead to cirrhosis and even hepatocellular carcinoma in individuals who do not have a history of alcohol abuse. Aging increases the prevalence of NAFLD and is strongly associated with the progression and severity of this disease. End-stage hepatic failure and liver cancer resulting from advanced NAFLD are leading indications for liver transplantation enhancing the burden on our healthcare systems. Accumulating clinical evidence also suggests that patients with NAFLD have a higher prevalence of cardiovascular disease. Pathogenetic mechanisms involved in the development and progression of NAFLD are poorly understood and as such, there is a lack of effective therapies. The common marmoset is a relatively short-lived non-human primate that recapitulates many of the physiological changes that occur in human aging. We hypothesized an age-associated increase in hepatic steatosis and alterations in serum lipid profile in the marmoset model. An increase in triglyceride levels and oil red o staining in liver tissues of old marmosets compared to young animals was observed suggesting an age-associated increase in hepatic steatosis in marmosets as observed in humans. Lipidomic studies were also performed using blood samples from male and female marmosets to investigate age-associated changes in specific lipid species, which are characteristic of aberrant lipid metabolism. Analysis of the results revealed significant decreases in several phosphatidylethanolamine, phosphatidylcholine, and sphingomyelin species in the plasma of old marmosets compared to young marmosets. We are now performing studies to determine whether the observed changes in different lipid species could influence the development of cardiovascular disease and provide new insights underlying the mechanisms of NAFLD development with aging.

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Association of Serum Lipoprotein-Associated Phospholipase A2 Level with Nonalcoholic Fatty Liver Disease

Metabolic Syndrome and Related Disorders ◽

10.1089/met.2011.0111 ◽

2012 ◽

Vol 10 (2) ◽

pp. 103-109 ◽

Cited By ~ 7

Author(s):

Yasar Colak ◽

Ebubekir Senates ◽

Oguzhan Ozturk ◽

Hamdi Levent Doganay ◽

Ender Coskunpinar ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Phospholipase A2 ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Serum Lipoprotein ◽

Nonalcoholic Fatty Liver

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Establishment of an ex Vivo Model of Nonalcoholic Fatty Liver Disease Using a Tissue-Engineered Liver

ACS Biomaterials Science & Engineering ◽

10.1021/acsbiomaterials.8b00652 ◽

2018 ◽

Vol 4 (8) ◽

pp. 3016-3026 ◽

Cited By ~ 3

Author(s):

Qiao Wu ◽

Juan Liu ◽

Lijin Liu ◽

Yu Chen ◽

Jie Wang ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Ex Vivo ◽

Ex Vivo Model ◽

Nonalcoholic Fatty Liver

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Lipid mediators of liver injury in nonalcoholic fatty liver disease

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00170.2018 ◽

2019 ◽

Vol 316 (1) ◽

pp. G75-G81 ◽

Cited By ~ 12

Author(s):

Suthat Liangpunsakul ◽

Naga Chalasani

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Cell Injury ◽

Lipid Mediators ◽

Severe Liver ◽

Nonalcoholic Fatty Liver ◽

Lipid Species ◽

Severe Liver Disease

Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of histopathological phenotypes ranging from simple steatosis to more severe liver disease associated with cell injury, including nonalcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis. Only a subset of patients with NAFLD develop NASH from yet incompletely understood mechanisms. Emerging data suggest lipid species other than triglycerides as contributors to the pathogenesis of NASH. In this mini review, we focus on the recent data on the mechanisms of NASH, focusing on these lipid mediators and their potential as therapeutic targets in NASH.

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