Mexican Ganoderma Lucidum Extracts Decrease Lipogenesis Modulating Transcriptional Metabolic Networks and Gut Microbiota in C57BL/6 Mice Fed with a High-Cholesterol Diet

Prevention of hyperlipidemia and associated diseases is a health priority. Natural products, such as the medicinal mushroom Ganoderma lucidum (Gl), have demonstrated hypocholesterolemic, prebiotic and antidiabetic properties. However, the underlying transcriptomic mechanisms by which Gl exerts bioactivities are not completely understood. We report a comprehensive hepatic and renal transcriptome profiling of C57BL/6 mice under the consumption of a high-cholesterol diet and two standardized Gl extracts obtained from basidiocarps cultivated on conventional substrate (Gl-1) or substrate containing acetylsalicylic acid (ASA; Gl-2). We showed that Gl extracts modulate relevant metabolic pathways involving the restriction of lipid biosynthesis and the enrichment of lipid degradation and secretion. The Gl-2 extract exerts a major modulation over gene expression programs showing the highest similarity with simvastatin druggable-target-genes and these are enriched more in processes related to human obesity alterations in the liver. We further show a subset of Gl-modulated genes correlated with Lactobacillus enrichment and the reduction of circulating cholesterol-derived fats. Moreover, Gl extracts induce a significant decrease of macrophage lipid storage, which occurs concomitantly with the down-modulation of Fasn and Elovl6. Collectively, this evidence suggests a new link between Gl hypocholesterolemic and prebiotic activity, revealing thereby that standardized Mexican Gl extracts are a novel transcriptome modulator to prevent metabolic disorders associated with hypercholesterolemia.

Download Full-text

Impact of SCP-2/SCP-x gene ablation and dietary cholesterol on hepatic lipid accumulation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00460.2014 ◽

2015 ◽

Vol 309 (5) ◽

pp. G387-G399 ◽

Cited By ~ 22

Author(s):

Devon Klipsic ◽

Danilo Landrock ◽

Gregory G. Martin ◽

Avery L. McIntosh ◽

Kerstin K. Landrock ◽

...

Keyword(s):

Fatty Acid ◽

Cholesteryl Ester ◽

Hepatic Steatosis ◽

Target Genes ◽

High Cholesterol Diet ◽

Carrier Protein ◽

Sterol Carrier Protein ◽

Cholesterol Diet ◽

High Cholesterol ◽

Fatty Acid Binding

While a high-cholesterol diet induces hepatic steatosis, the role of intracellular sterol carrier protein-2/sterol carrier protein-x (SCP-2/SCP-x) proteins is unknown. We hypothesized that ablating SCP-2/SCP-x [double knockout (DKO)] would impact hepatic lipids (cholesterol and cholesteryl ester), especially in high-cholesterol-fed mice. DKO did not alter food consumption, and body weight (BW) gain decreased especially in females, concomitant with hepatic steatosis in females and less so in males. DKO-induced steatosis in control-fed wild-type (WT) mice was associated with 1) loss of SCP-2; 2) upregulation of liver fatty acid binding protein (L-FABP); 3) increased mRNA and/or protein levels of sterol regulatory element binding proteins (SREBP1 and SREBP2) as well as increased expression of target genes of cholesterol synthesis ( Hmgcs1 and Hmgcr) and fatty acid synthesis ( Acc1 and Fas); and 4) cholesteryl ester accumulation was also associated with increased acyl-CoA cholesterol acyltransferase-2 (ACAT2) in males. DKO exacerbated the high-cholesterol diet-induced hepatic cholesterol and glyceride accumulation, without further increasing SREBP1, SREBP2, or target genes. This exacerbation was associated both with loss of SCP-2 and concomitant downregulation of Ceh/Hsl, apolipoprotein B (ApoB), MTP, and/or L-FABP protein expression. DKO diminished the ability to secrete excess cholesterol into bile and oxidize cholesterol to bile acid for biliary excretion, especially in females. This suggested that SCP-2/SCP-x affects cholesterol transport to particular intracellular compartments, with ablation resulting in less to the endoplasmic reticulum for SREBP regulation, making more available for cholesteryl ester synthesis, for cholesteryl-ester storage in lipid droplets, and for bile salt synthesis and/or secretion. These alterations are significant findings, since they affect key processes in regulation of sterol metabolism.

Download Full-text

Efficacy of Ganoderma lucidum on plasma lipids and lipoproteins in rats fed with high cholesterol diet

Nutrition & Food Science ◽

10.1108/00346650810871911 ◽

2008 ◽

Vol 38 (3) ◽

pp. 229-238 ◽

Cited By ~ 3

Author(s):

Chow‐Chin Tong ◽

Yew‐Keong Choong ◽

Suhaila Mohamed ◽

Noordin Mohamed Mustapha ◽

Nor Aini Umar

Keyword(s):

Ganoderma Lucidum ◽

Plasma Lipids ◽

High Cholesterol Diet ◽

Cholesterol Diet ◽

High Cholesterol ◽

Lipids And Lipoproteins

Download Full-text

Cholesterol 7α-hydroxylase-deficient mice are protected from high-fat/high-cholesterol diet-induced metabolic disorders

The Journal of Lipid Research ◽

10.1194/jlr.m064709 ◽

2016 ◽

Vol 57 (7) ◽

pp. 1144-1154 ◽

Cited By ~ 32

Author(s):

Jessica M. Ferrell ◽

Shannon Boehme ◽

Feng Li ◽

John Y. L. Chiang

Keyword(s):

Metabolic Disorders ◽

High Cholesterol Diet ◽

Cholesterol Diet ◽

High Cholesterol ◽

High Fat ◽

Deficient Mice

Download Full-text

High-Lard and High-Cholesterol Diet, but not High-Lard Diet, Leads to Metabolic Disorders in a Modified Dyslipidemia Model

Arquivos Brasileiros de Cardiologia ◽

10.5935/abc.20190149 ◽

2019 ◽

Cited By ~ 1

Author(s):

Lidiane B. Muniz ◽

Aline M. Alves-Santos ◽

Fabricio Camargo ◽

Danieli Brolo Martins ◽

Mara Rubia N. Celes ◽

...

Keyword(s):

Metabolic Disorders ◽

High Cholesterol Diet ◽

Cholesterol Diet ◽

High Cholesterol ◽

Lard Diet

Download Full-text

Modulatory Effect of Chaetomorpha gracilis on Erythrocytes Functions and Metabolic Disorders in Mice Fed a High-cholesterol Diet

Journal of Oleo Science ◽

10.5650/jos.ess20104 ◽

2021 ◽

Vol 70 (6) ◽

pp. 837-848

Author(s):

Noura Brahmi ◽

Houda Hamed ◽

Chomous Kallel ◽

Aida Elleuch ◽

Fatma Makni Ayadi ◽

...

Keyword(s):

Metabolic Disorders ◽

High Cholesterol Diet ◽

Cholesterol Diet ◽

High Cholesterol

Download Full-text

Metabolic Profiling Reveals Aggravated Non-Alcoholic Steatohepatitis in High-Fat High-Cholesterol Diet-Fed Apolipoprotein E-Deficient Mice Lacking Ron Receptor Signaling

Metabolites ◽

10.3390/metabo10080326 ◽

2020 ◽

Vol 10 (8) ◽

pp. 326

Author(s):

Joselyn N. Allen ◽

Adwitia Dey ◽

Jingwei Cai ◽

Jingtao Zhang ◽

Yuan Tian ◽

...

Keyword(s):

Lipid Metabolism ◽

Apolipoprotein E ◽

Metabolic Pathways ◽

Receptor Activation ◽

High Cholesterol Diet ◽

Cholesterol Diet ◽

High Cholesterol ◽

High Fat ◽

Alcoholic Steatohepatitis ◽

Ron Receptor

Non-alcoholic steatohepatitis (NASH) represents the progressive sub-disease of non-alcoholic fatty liver disease that causes chronic liver injury initiated and sustained by steatosis and necroinflammation. The Ron receptor is a tyrosine kinase of the Met proto-oncogene family that potentially has a beneficial role in adipose and liver-specific inflammatory responses, as well as glucose and lipid metabolism. Since its discovery two decades ago, the Ron receptor has been extensively investigated for its differential roles on inflammation and cancer. Previously, we showed that Ron expression on tissue-resident macrophages limits inflammatory macrophage activation and promotes a repair phenotype, which can retard the progression of NASH in a diet-induced mouse model. However, the metabolic consequences of Ron activation have not previously been investigated. Here, we explored the effects of Ron receptor activation on major metabolic pathways that underlie the development and progression of NASH. Mice lacking apolipoprotein E (ApoE KO) and double knockout (DKO) mice that lack ApoE and Ron were maintained on a high-fat high-cholesterol diet for 18 weeks. We observed that, in DKO mice, the loss of ligand-dependent Ron signaling aggravated key pathological features in steatohepatitis, including steatosis, inflammation, oxidation stress, and hepatocyte damage. Transcriptional programs positively regulating fatty acid (FA) synthesis and uptake were upregulated in the absence of Ron receptor signaling, whereas lipid disposal pathways were downregulated. Consistent with the deregulation of lipid metabolism pathways, the DKO animals exhibited increased accumulation of FAs in the liver and decreased level of bile acids. Altogether, ligand-dependent Ron receptor activation provides protection from the deregulation of major metabolic pathways that initiate and aggravate non-alcoholic steatohepatitis.

Download Full-text