MicroRNAs regulating lipid metabolism in atherogenesis

SummaryMicroRNAs have emerged as important post-transcriptional regulators of lipid metabolism, and represent a new class of targets for therapeutic intervention. Recently, microRNA-33a and b (miR-33a/b) were discovered as key regulators of metabolic programs including cholesterol and fatty acid homeostasis. These intronic microRNAs are embedded in the sterol response element binding protein genes, SREBF2 and SREBF1, which code for transcription factors that coordinate cholesterol and fatty acid synthesis. By repressing a variety of genes involved in cholesterol export and fatty acid oxidation, including ABCA1, CROT, CPT1, HADHB and PRKAA1, miR-33a/b act in concert with their host genes to boost cellular sterol levels. Recent work in animal models has shown that inhibition of these small non-coding RNAs has potent effects on lipoprotein metabolism, including increasing plasma high-density lipo-protein (HDL) and reducing very low density lipoprotein (VLDL) triglyce-rides. Furthermore, other microRNAs are being discovered that also target the ABCA1 pathway, including miR-758, suggesting that miRNAs may work cooperatively to regulate this pathway. These exciting findings support the development of microRNA antagonists as potential therapeutics for the treatment of dyslipidaemia, atherosclerosis and related metabolic diseases.

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ChREBP-Mediated Regulation of Lipid Metabolism: Involvement of the Gut Microbiota, Liver, and Adipose Tissue

Frontiers in Endocrinology ◽

10.3389/fendo.2020.587189 ◽

2020 ◽

Vol 11 ◽

Author(s):

Katsumi Iizuka ◽

Ken Takao ◽

Daisuke Yabe

Keyword(s):

Adipose Tissue ◽

Fatty Acid ◽

Lipid Metabolism ◽

Gut Microbiota ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Acid Synthesis ◽

Whole Body ◽

Acetyl Coa ◽

Alcoholic Fatty Liver

Carbohydrate response element-binding protein (ChREBP) plays an important role in the development of type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease, as well as tumorigenesis. ChREBP is highly expressed in lipogenic organs, such as liver, intestine, and adipose tissue, in which it regulates the production of acetyl CoA from glucose by inducing Pklr and Acyl expression. It has recently been demonstrated that ChREBP plays a role in the conversion of gut microbiota-derived acetate to acetyl CoA by activating its target gene, Acss2, in the liver. ChREBP regulates fatty acid synthesis, elongation, and desaturation by inducing Acc1 and Fasn, elongation of long-chain fatty acids family member 6 (encoded by Elovl6), and Scd1 expression, respectively. ChREBP also regulates the formation of very low-density lipoprotein by inducing the expression of Mtp. Furthermore, it plays a crucial role in peripheral lipid metabolism by inducing Fgf21 expression, as well as that of Angptl3 and Angptl8, which are known to reduce peripheral lipoprotein lipase activity. In addition, ChREBP is involved in the production of palmitic-acid-5-hydroxystearic-acid, which increases insulin sensitivity in adipose tissue. Curiously, ChREBP is indirectly involved in fatty acid β-oxidation and subsequent ketogenesis. Thus, ChREBP regulates whole-body lipid metabolism by controlling the transcription of lipogenic enzymes and liver-derived cytokines.

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Leptin Augments the Acute Suppressive Effects of Insulin on Hepatic Very Low-Density Lipoprotein Production in Rats

Endocrinology ◽

10.1210/en.2008-1271 ◽

2009 ◽

Vol 150 (5) ◽

pp. 2169-2174 ◽

Cited By ~ 13

Author(s):

Wan Huang ◽

Anantha Metlakunta ◽

Nikolas Dedousis ◽

Heidi K. Ortmeyer ◽

Maja Stefanovic-Racic ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Oxidation ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Saline Control ◽

Acid Oxidation ◽

Very Low Density Lipoprotein ◽

Low Density ◽

Vldl Metabolism

It is well established that leptin increases the sensitivity of carbohydrate metabolism to the effects of insulin. Leptin and insulin also have potent effects on lipid metabolism. However, the effects of leptin on the regulation of liver lipid metabolism by insulin have not been investigated. The current study addressed the effects of leptin on insulin-regulated hepatic very low-density lipoprotein (VLDL) metabolism in vivo in rats. A 90-min hyperinsulinemic/euglycemic clamp (4 mU/kg · min−1) reduced plasma VLDL triglyceride (TG) by about 50% (P < 0.001 vs. saline control). Importantly, a leptin infusion (0.2 μg/kg · min−1) in combination with insulin reduced plasma VLDL-TG by about 80% (P < 0.001 vs. insulin alone). These effects did not require altered skeletal muscle lipoprotein lipase activity but did include differential effects of insulin and leptin on liver apolipoprotein (apo) B and TG metabolism. Thus, insulin decreased liver and plasma apoB100/B48 levels (∼50%, P < 0.01), increased liver TGs (∼20%, P < 0.05), and had no effect on fatty acid oxidation. Conversely, leptin decreased liver TGs (∼50%, P < 0.01) and increased fatty acid oxidation (∼50%, P < 0.01) but had no effects on liver or plasma apoB levels. Importantly, the TG-depleting and prooxidative effects of leptin were maintained in the presence of insulin. We conclude that leptin additively increases the suppressive effects of insulin on hepatic and systemic VLDL metabolism by stimulating depletion of liver TGs and increasing oxidative metabolism. The net effect of the combined actions of insulin and leptin is to decrease the production and TG content of VLDL particles.

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Inhibition of fatty acid synthesis decreases very low density lipoprotein secretion in the hamster.

The Journal of Lipid Research ◽

10.1016/s0022-2275(20)41509-3 ◽

1992 ◽

Vol 33 (6) ◽

pp. 843-851

Author(s):

CM Arbeeny ◽

DS Meyers ◽

KE Bergquist ◽

RE Gregg

Keyword(s):

Fatty Acid ◽

Fatty Acid Synthesis ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Acid Synthesis ◽

Very Low Density Lipoprotein ◽

Low Density ◽

Lipoprotein Secretion

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Efficacy and Mechanism of a Chinese Classic Prescription of Yueju in Treating Nonalcoholic Steatohepatitis and Protecting Hepatocytes from Apoptosis

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/8888040 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Xiao-Li He ◽

Yan-Ming He ◽

Dan Zhang ◽

Hong-Shan Li ◽

Qiang Zhang ◽

...

Keyword(s):

Lipid Metabolism ◽

Nonalcoholic Steatohepatitis ◽

Fatty Acid Synthase ◽

Metabolic Diseases ◽

Smooth Muscle Actin ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

High Cholesterol Diet ◽

Apoptosis Protein ◽

Abnormal Lipid Metabolism

Yueju, a famous classic Chinese prescription, has been extensively used in treating depression syndromes for hundreds of years. Recent studies have reported that Yueju showed good effects in treating metabolic diseases, such as obesity and hyperlipidemia. Nonalcoholic steatohepatitis (NASH), which leads to cirrhosis and severe cardiovascular diseases, is closely linked to obesity and abnormal lipid metabolism. In this study, Yueju could decrease the levels of alanine aminotransferase, aspartate transaminase, triglyceride, cholesterol, and low-density lipoprotein-C but increase the high-density lipoprotein-C in the serum of the NASH rat model induced by high-fat and high-cholesterol diet. Yueju could alleviate hepatosteatosis by increasing the phosphorylation of acetyl-CoA carboxylase and inhibiting the expression of fatty acid synthase and stearoyl-CoA desaturase 1. Yueju downregulated the expression of α-smooth muscle actin and collagen type 1A1, ameliorating the liver fibrilization. Yueju could also protect the hepatocytes from apoptosis by upregulating antiapoptosis protein Bcl-2 and X-linked inhibitor of apoptosis protein and downregulating apoptotic proteins Bax and cleaved poly ADP-ribose polymerase. Thus, Yueju could improve liver function, regulate lipid metabolism, alleviate hepatosteatosis and fibrosis, and protect hepatocytes from apoptosis against NASH. Yueju may be used as an alternative effective medicine for NASH treatment.

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Maternal diets deficient in folic acid and related methyl donors modify mechanisms associated with lipid metabolism in the fetal liver of the rat

British Journal Of Nutrition ◽

10.1017/s0007114509990389 ◽

2009 ◽

Vol 102 (10) ◽

pp. 1445-1452 ◽

Cited By ~ 10

Author(s):

Christopher J. McNeil ◽

Susan M. Hay ◽

Garry J. Rucklidge ◽

Martin D. Reid ◽

Gary J. Duncan ◽

...

Keyword(s):

Folic Acid ◽

Fatty Acid ◽

Lipid Metabolism ◽

Fetal Liver ◽

Acid Synthesis ◽

Pregnant Rat ◽

Methyl Donors ◽

Indirect Response ◽

Element Binding Protein ◽

Mitochondrial Oxidation

Previously we have examined the effects of diets deficient in folic acid ( − F) or folate deficient with low methionine and choline ( − F LM LC) on the relative abundance of soluble proteins in the liver of the pregnant rat. In the present study we report the corresponding changes in the fetal liver at day 21 of gestation. The abundance of eighteen proteins increased when dams were fed the − F diet. When dams were fed the − F LM LC diet, thirty-three proteins increased and eight decreased. Many of the differentially abundant proteins in the fetal liver could be classified into the same functional groups as those previously identified in the maternal liver, namely protein synthesis, metabolism, lipid metabolism and proteins associated with the cytoskeleton and endoplasmic reticulum. The pattern was consistent with reduced cell proliferation in the − F LM LC group but not in the − F group. Metabolic enzymes associated with lipid metabolism changed in both the − F and − F LM LC groups. The mRNA for carnitine palmitoyl transferase were up-regulated and CD36 (fatty acid translocase) down-regulated in the − F group, suggesting increased mitochondrial oxidation of fatty acids as an indirect response to altered maternal lipid metabolism. In the − F LM LC group the mRNA for acetyl CoA carboxylase was down-regulated, suggesting reduced fatty acid synthesis. The mRNA for transcriptional regulators including PPARα and sterol response element-binding protein-1c were unchanged. These results suggest that an adequate supply of folic acid and the related methyl donors may benefit fetal development directly by improving lipid metabolism in fetal as well as maternal tissues.

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Adenovirus-Mediated High Expression of Resistin Causes Dyslipidemia in Mice

Endocrinology ◽

10.1210/en.2004-0985 ◽

2005 ◽

Vol 146 (1) ◽

pp. 273-279 ◽

Cited By ~ 53

Author(s):

Naoichi Sato ◽

Kunihisa Kobayashi ◽

Toyoshi Inoguchi ◽

Noriyuki Sonoda ◽

Minako Imamura ◽

...

Keyword(s):

Lipid Metabolism ◽

Phosphoenolpyruvate Carboxykinase ◽

Low Density Lipoprotein ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Glucose Production ◽

Low Density ◽

Adenoviral Gene Transfer ◽

Insulin Resistant

The adipocyte-derived hormone resistin has been proposed as a possible link between obesity and insulin resistance in murine models. Many recent studies have reported physiological roles for resistin in glucose homeostasis, one of which is enhancement of glucose production from the liver by up-regulating gluconeogenic enzymes such as glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. However, its in vivo roles in lipid metabolism still remain to be clarified. In this study, we investigated the effects of resistin overexpression on insulin action and lipid metabolism in C57BL/6 mice using an adenoviral gene transfer technique. Elevated plasma resistin levels in mice treated with the resistin adenovirus (AdmRes) were confirmed by Western blotting analysis and RIAs. Fasting plasma glucose levels did not differ between AdmRes-treated mice and controls, but the basal insulin concentration was significantly elevated in AdmRes-treated mice. In AdmRes-treated mice, the glucose-lowering effect of insulin was impaired, as evaluated by insulin tolerance tests. Furthermore, total cholesterol and triglyceride concentrations were significantly higher, whereas the high-density lipoprotein cholesterol level was significantly lower. Lipoprotein analysis revealed that low-density lipoprotein was markedly increased in AdmRes-treated mice, compared with controls. In addition, in vivo Triton WR-1339 studies showed evidence of enhanced very low-density lipoprotein production in AdmRes-treated mice. The expressions of genes involved in lipoprotein metabolism, such as low-density lipoprotein receptor and apolipoprotein AI in the liver, were decreased. These results suggest that resistin overexpression induces dyslipidemia in mice, which is commonly seen in the insulin-resistant state, partially through enhanced secretion of lipoproteins.

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Lipid metabolism in golden hamsters infected with plerocercoids of Spirometra erinacei (Cestoda: Pseudophyllidea)

Parasitology ◽

10.1017/s0031182000049891 ◽

1986 ◽

Vol 93 (1) ◽

pp. 143-151 ◽

Cited By ~ 10

Author(s):

T. Tsuboi ◽

K. Hirai

Keyword(s):

Fatty Acid ◽

Lipase Activity ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Acid Synthesis ◽

Immunoreactive Insulin ◽

Synthetase Activity ◽

Production Studies ◽

Golden Hamsters ◽

Spirometra Erinacei

SUMMARYGolden hamsters infected with Spirometra erinacei plerocercoids develop a hypertriglyceridaemia characterized by an increase in very low-density lipoprotein. Acyl-CoA synthetase activity, the rate of fatty acid synthesis in the liver and triglyceride production studies showed that the activation and synthesis of fatty acid and production of triglyceride in plerocercoidinfected hamsters were not significantly different from the controls. Lipase activity in post-heparin plasma was found to be suppressed in plerocercoid-infected golden hamsters. The presence of plerocercoids also resulted in a significant reduction in serum thyroxine, but the hypertriglyceridaemia associated with plerocercoid infection was not reversed by injecting the infected hamsters with 2 μg/ day doses of L-thyroxine. The levels of serum immunoreactive insulin in plerocercoid-infected hamsters were not significantly different from the controls. We conclude that the hypertriglyceridaemia, associated with plerocercoid infection in hamsters, results predominantly from a suppression of triglyceride degradation, and that the suppression of lipase activity is probably not the result of hypothyroidism or the lack of insulin, but the result of secretion of growth hormone-like substances.

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Analysis of mycobacterial infection-induced changes to host lipid metabolism in a zebrafish infection model reveals a conserved role for LDLR in infection susceptibility

10.1101/250548 ◽

2018 ◽

Author(s):

Matt D. Johansen ◽

Elinor Hortle ◽

Joshua A. Kasparian ◽

Alejandro Romero ◽

Beatriz Novoa ◽

...

Keyword(s):

Lipid Metabolism ◽

Low Density Lipoprotein ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Mycobacterial Infection ◽

Infection Model ◽

Zebrafish Model ◽

Marine Research ◽

Functional Relevance ◽

Induced Changes

AbstractChanges to lipid metabolism are well-characterised consequences of human tuberculosis infection but their functional relevance are not clearly elucidated in these or other host-mycobacterial systems. The zebrafish-Mycobacterium marinum infection model is used extensively to model many aspects of human-M. tuberculosis pathogenesis but has not been widely used to study the role of infection-induced lipid metabolism. We find mammalian mycobacterial infection-induced alterations in host Low Density Lipoprotein metabolism are conserved in the zebrafish model of mycobacterial pathogenesis. Depletion of LDLR, a key lipid metabolism node, decreased M. marinum burden, and corrected infection-induced altered lipid metabolism resulting in decreased LDL and reduced the rate of macrophage transformation into foam cells. Our results demonstrate a conserved role for infection-induced alterations to host lipid metabolism, and specifically the LDL-LDLR axis, across host-mycobacterial species pairings.FundingThis work was supported by the Australian National Health and Medical Research Council (APP1099912 and APP1053407 to S.H.O.); Meat and Livestock Australia (P.PSH. 0813 to A.C.P. and K. dS); the Marie Bashir Institute for Infectious Diseases and Biosecurity (grant to S.H.O., A.C.P. and K. dS); the Kenyon Family Foundation Inflammation Award (grant to S.H.O.); the University of Sydney (fellowship to S.H.O.); Consellería de Economía, Emprego e Industria (GAIN), Xunta de Galicia (grant IN607B 2016/12 to Institute of Marine Research (IIM-CSIC)).

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Staphylococcus aureusUtilizes Host-Derived Lipoprotein Particles as Sources of Fatty Acids

Journal of Bacteriology ◽

10.1128/jb.00728-17 ◽

2018 ◽

Vol 200 (11) ◽

Cited By ~ 18

Author(s):

Phillip C. Delekta ◽

John C. Shook ◽

Todd A. Lydic ◽

Martha H. Mulks ◽

Neal D. Hammer

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Synthesis ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Acid Synthesis ◽

Low Density ◽

Content Type ◽

Lipoprotein Particles ◽

Bacterial Fatty Acid

ABSTRACTMethicillin-resistantStaphylococcus aureus(MRSA) is a threat to global health. Consequently, much effort has focused on the development of new antimicrobials that target novel aspects ofS. aureusphysiology. Fatty acids are required to maintain cell viability, and bacteria synthesize fatty acids using the type II fatty acid synthesis (FASII) pathway. FASII is significantly different from human fatty acid synthesis, underscoring the therapeutic potential of inhibiting this pathway. However, many Gram-positive pathogens incorporate exogenous fatty acids, bypassing FASII inhibition and leaving the clinical potential of FASII inhibitors uncertain. Importantly, the source(s) of fatty acids available to pathogens within the host environment remains unclear. Fatty acids are transported throughout the body by lipoprotein particles in the form of triglycerides and esterified cholesterol. Thus, lipoproteins, such as low-density lipoprotein (LDL), represent a potentially rich source of exogenous fatty acids forS. aureusduring infection. We sought to test the ability of LDLs to serve as a fatty acid source forS. aureusand show that cells cultured in the presence of human LDLs demonstrate increased tolerance to the FASII inhibitor triclosan. Using mass spectrometry, we observed that host-derived fatty acids present in the LDLs are incorporated into the staphylococcal membrane and that tolerance to triclosan is facilitated by the fatty acid kinase A, FakA, and Geh, a triacylglycerol lipase. Finally, we demonstrate that human LDLs support the growth ofS. aureusfatty acid auxotrophs. Together, these results suggest that human lipoprotein particles are a viable source of exogenous fatty acids forS. aureusduring infection.IMPORTANCEInhibition of bacterial fatty acid synthesis is a promising approach to combating infections caused byS. aureusand other human pathogens. However,S. aureusincorporates exogenous fatty acids into its phospholipid bilayer. Therefore, the clinical utility of targeting bacterial fatty acid synthesis is debated. Moreover, the fatty acid reservoir(s) exploited byS. aureusis not well understood. Human low-density lipoprotein particles represent a particularly abundantin vivosource of fatty acids and are present in tissues thatS. aureuscolonizes. Herein, we establish thatS. aureusis capable of utilizing the fatty acids present in low-density lipoproteins to bypass both chemical and genetic inhibition of fatty acid synthesis. These findings imply thatS. aureustargets LDLs as a source of fatty acids during pathogenesis.

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