ACSS2 promotes systemic fat storage and utilization through selective regulation of genes involved in lipid metabolism

Acetyl-CoA synthetase 2 (ACSS2) is a conserved nucleocytosolic enzyme that converts acetate to acetyl-CoA. Adult mice lacking ACSS2 appear phenotypically normal but exhibit reduced tumor burdens in mouse models of liver cancer. The normal physiological functions of this alternate pathway of acetyl-CoA synthesis remain unclear, however. Here, we reveal that mice lacking ACSS2 exhibit a significant reduction in body weight and hepatic steatosis in a diet-induced obesity model. ACSS2 deficiency reduces dietary lipid absorption by the intestine and also perturbs repartitioning and utilization of triglycerides from adipose tissue to the liver due to lowered expression of lipid transporters and fatty acid oxidation genes. In this manner, ACSS2 promotes the systemic storage or metabolism of fat according to the fed or fasted state through the selective regulation of genes involved in lipid metabolism. Thus, targeting ACSS2 may offer a therapeutic benefit for the treatment of fatty liver disease.

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Investigating the Role Intestinal-Specific FXR and SHP in Regulating Lipid Metabolism in Mice

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1649 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A810-A810

Author(s):

James ThienToan Nguyen ◽

Sayeepriyadarshini Anakk

Keyword(s):

Lipid Metabolism ◽

Bile Acid ◽

Farnesoid X Receptor ◽

Dietary Fats ◽

Lipid Absorption ◽

Mice Model ◽

Simple Diffusion ◽

Bile Acid Concentration ◽

Lipid Transporters

Abstract Dysregulation of lipid metabolism is a causal factor that can lead to a variety of disorders, such as obesity and metabolic syndrome. Dietary fats are digested in the small intestine by the physiological detergents known as bile acids. They emulsify the fats and break them down into smaller molecules in order for the enterocytes to absorb the nutrients through simple diffusion or through the utilization of specific lipid transporters. Interestingly, the nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP) not only regulates bile acid synthesis and circulation, but also lipid metabolism. Although many studies have examined the role of FXR in hepatic and intestinal lipid metabolism, studies investigating the role of SHP in the intestine are still lacking. Although FXR and SHP cooperate to regulate many metabolic pathways, FXR or SHP knockout models exhibit different lipid phenotypes. These data indicate there are FXR-dependent and -independent pathways of SHP that controls lipid metabolism. To delineate these two interconnecting yet separate pathways, we will utilize intestine-specific Shp knockout (IShpKO) and intestine-specific Fxr knockout (IFxrKO) mice model and place them on high fat diet to investigate their intestinal intestinal absorption and transportation of lipids. We will also monitor the bile acid pool in the intestine, serum, and liver in these knockouts to evaluate the consequence of intestinal deletion of Fxr as well as Shp on bile acid homeostasis and how this may affect lipid absorption. These experiments will identify how FXR and/or SHP regulates intestinal fat digestion and absorption and if this is secondary to the alterations in bile acid concentration and lipid transporters. In addition, we will also investigate the intestinal Fxr-Shp double knockout (IDKO) mice model to determine their combined contribution in intestinal lipid metabolism. Overall, the results obtained from this research will elucidate if intestinal FXR and SHP cooperate or can independently regulate lipid metabolism and homeostasis.

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Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity

Nature Communications ◽

10.1038/s41467-019-13180-8 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 8

Author(s):

Mercedes Dávalos-Salas ◽

Magdalene K. Montgomery ◽

Camilla M. Reehorst ◽

Rebecca Nightingale ◽

Irvin Ng ◽

...

Keyword(s):

Lipid Metabolism ◽

Intestinal Epithelium ◽

Acid Oxidation ◽

Intestinal Epithelial ◽

Histone Deacetylase 3 ◽

Diet Induced Obesity ◽

Ppar Agonists ◽

Lipid Metabolism Genes ◽

Long Chain Triglycerides ◽

Specific Deletion

AbstractHistone deacetylase 3 (Hdac3) regulates the expression of lipid metabolism genes in multiple tissues, however its role in regulating lipid metabolism in the intestinal epithelium is unknown. Here we demonstrate that intestine-specific deletion of Hdac3 (Hdac3IKO) protects mice from diet induced obesity. Intestinal epithelial cells (IECs) from Hdac3IKO mice display co-ordinate induction of genes and proteins involved in mitochondrial and peroxisomal β-oxidation, have an increased rate of fatty acid oxidation, and undergo marked remodelling of their lipidome, particularly a reduction in long chain triglycerides. Many HDAC3-regulated fatty oxidation genes are transcriptional targets of the PPAR family of nuclear receptors, Hdac3 deletion enhances their induction by PPAR-agonists, and pharmacological HDAC3 inhibition induces their expression in enterocytes. These findings establish a central role for HDAC3 in co-ordinating PPAR-regulated lipid oxidation in the intestinal epithelium, and identify intestinal HDAC3 as a potential therapeutic target for preventing obesity and related diseases.

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Effects of dietary lipid level on growth, fatty acid profiles, antioxidant capacity and expression of genes involved in lipid metabolism in juvenile swimming crab, Portunus trituberculatus

British Journal Of Nutrition ◽

10.1017/s0007114519002563 ◽

2019 ◽

Vol 123 (2) ◽

pp. 149-160 ◽

Cited By ~ 5

Author(s):

Peng Sun ◽

Min Jin ◽

Lefei Jiao ◽

Óscar Monroig ◽

Juan Carlos Navarro ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Lipid Level ◽

Dietary Lipid ◽

The Other ◽

Acid Oxidation ◽

Swimming Crab ◽

Lipid Levels ◽

Expression Of Genes ◽

Dietary Lipid Level

AbstractThe regulation of lipogenesis and lipolysis mechanisms related to consumption of lipid has not been studied in swimming crab. The aims of the present study were to evaluate the effects of dietary lipid levels on growth, enzymes activities and expression of genes of lipid metabolism in hepatopancreas of juvenile swimming crab. Three isonitrogenous diets were formulated to contain crude lipid levels at 5·8, 9·9 and 15·1 %. Crabs fed the diet containing 15·1 % lipid had significantly lower growth performance and feed utilisation than those fed the 5·8 and 9·9 % lipid diets. Crabs fed 5·8 % lipid had lower malondialdehyde concentrations in the haemolymph and hepatopancreas than those fed the other diets. Highest glutathione peroxidase in haemolymph and superoxide dismutase in hepatopancreas were observed in crabs fed 5·8 % lipid. The lowest fatty acid synthase and glucose 6-phosphate dehydrogenase activities in hepatopancreas were observed in crabs fed 15·1 % lipid, whereas crabs fed 5·8 % lipid had lower carnitine palmitoyltransferase-1 activity than those fed the other diets. Crabs fed 15·1 % lipid showed lower hepatopancreas expression of genes involved in long-chain-PUFA biosynthesis, lipoprotein clearance, fatty acid uptake, fatty acid oxidation, lipid anabolism and lipid catabolism than those fed the other diets, whereas expression of some genes of lipoprotein assembly and fatty acid oxidation was up-regulated compared with crabs fed 5·8 % lipid. Overall, high dietary lipid level can inhibit growth, reduce antioxidant enzyme activities and influence lipid metabolic pathways to regulate lipid deposition in crab.

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Circadian regulation of lipid metabolism

Proceedings of The Nutrition Society ◽

10.1017/s0029665116000288 ◽

2016 ◽

Vol 75 (4) ◽

pp. 440-450 ◽

Cited By ~ 42

Author(s):

Joshua J Gooley

Keyword(s):

Lipid Metabolism ◽

Energy Metabolism ◽

Circadian Rhythms ◽

Metabolic Pathways ◽

Circadian System ◽

Lipid Absorption ◽

Acid Oxidation ◽

Circadian Regulation ◽

Peripheral Tissues ◽

Lipid Species

The circadian system temporally coordinates daily rhythms in feeding behaviour and energy metabolism. The objective of the present paper is to review the mechanisms that underlie circadian regulation of lipid metabolic pathways. Circadian rhythms in behaviour and physiology are generated by master clock neurons in the suprachiasmatic nucleus (SCN). The SCN and its efferent targets in the hypothalamus integrate light and feeding signals to entrain behavioural rhythms as well as clock cells located in peripheral tissues, including the liver, adipose tissue and muscle. Circadian rhythms in gene expression are regulated at the cellular level by a molecular clock comprising a core set of clock genes/proteins. In peripheral tissues, hundreds of genes involved in lipid biosynthesis and fatty acid oxidation are rhythmically activated and repressed by clock proteins, hence providing a direct mechanism for circadian regulation of lipids. Disruption of clock gene function results in abnormal metabolic phenotypes and impaired lipid absorption, demonstrating that the circadian system is essential for normal energy metabolism. The composition and timing of meals influence diurnal regulation of metabolic pathways, with food intake during the usual rest phase associated with dysregulation of lipid metabolism. Recent studies using metabolomics and lipidomics platforms have shown that hundreds of lipid species are circadian-regulated in human plasma, including but not limited to fatty acids, TAG, glycerophospholipids, sterol lipids and sphingolipids. In future work, these lipid profiling approaches can be used to understand better the interaction between diet, mealtimes and circadian rhythms on lipid metabolism and risk for obesity and metabolic diseases.

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Carboxyl Ester Lipase Deficiency Exacerbates Dietary Lipid Absorption Abnormalities and Resistance to Diet-induced Obesity in Pancreatic Triglyceride Lipase Knockout Mice

Journal of Biological Chemistry ◽

10.1074/jbc.m702530200 ◽

2007 ◽

Vol 282 (34) ◽

pp. 24642-24649 ◽

Cited By ~ 25

Author(s):

Dean Gilham ◽

Eric D. Labonté ◽

Juan C. Rojas ◽

Ronald J. Jandacek ◽

Philip N. Howles ◽

...

Keyword(s):

Knockout Mice ◽

Dietary Lipid ◽

Lipid Absorption ◽

Triglyceride Lipase ◽

Diet Induced Obesity

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Cardiomyocyte-Restricted Deletion of PPARβ/δin PPARα-Null Mice Causes Impaired Mitochondrial Biogenesis and Defense, but No Further Depression of Myocardial Fatty Acid Oxidation

PPAR Research ◽

10.1155/2011/372854 ◽

2011 ◽

Vol 2011 ◽

pp. 1-13 ◽

Cited By ~ 12

Author(s):

Jian Liu ◽

Peiyong Wang ◽

Lan He ◽

Yuquan Li ◽

Jinwen Luo ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Oxidation ◽

Mitochondrial Biogenesis ◽

Acid Oxidation ◽

Key Factors ◽

Adult Mice ◽

Cardiac Phenotype ◽

Pathological Development

It is well documented that PPARαand PPARβ/δshare overlapping functions in regulating myocardial lipid metabolism. However, previous studies demonstrated that cardiomyocyte-restricted PPARβ/δdeficiency in mice leads to severe cardiac pathological development, whereas global PPARαknockout shows a benign cardiac phenotype. It is unknown whether a PPARα-null background would alter the pathological development in mice with cardiomyocyte-restricted PPARβ/δdeficiency. In the present study, a mouse model with long-term PPARβ/δdeficiency in PPARα-null background showed a comparably reduced cardiac expression of lipid metabolism to those of single PPAR-deficient mouse models. The PPARα-null background did not rescue or aggravate the cardiac pathological development linked to cardiomyocyte-restricted PPARβ/δdeficiency. Moreover, PPARα-null did not alter the phenotypic development in adult mice with the short-term deletion of PPARβ/δin their hearts, which showed mitochondrial abnormalities, depressed cardiac performance, and cardiac hypertrophy with attenuated expression of key factors in mitochondrial biogenesis and defense. The present study demonstrates that cardiomyocyte-restricted deletion of PPARβ/δin PPARα-null mice causes impaired mitochondrial biogenesis and defense, but no further depression of fatty acid oxidation. Therefore, PPARβ/δis essential for maintaining mitochondrial biogenesis and defense in cardiomyocytes independent of PPARα.

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Effect of the ACAA1 Gene on Preadipocyte Differentiation in Sheep

Frontiers in Genetics ◽

10.3389/fgene.2021.649140 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yanli Wang ◽

Xin Li ◽

Yang Cao ◽

Cheng Xiao ◽

Yu Liu ◽

...

Keyword(s):

Fatty Acid ◽

Lipid Metabolism ◽

Lipid Accumulation ◽

Fat Deposition ◽

Marker Genes ◽

Acid Oxidation ◽

Preadipocyte Differentiation ◽

Acetyl Coa ◽

Triglyceride Content ◽

Adipogenic Marker

Acetyl-CoA acyltransferase 1 (ACAA1) functions as a key regulator of fatty acid β-oxidation in peroxisomes by catalyzing the cleavage of 3-ketoacyl-CoA to acetyl-CoA and acyl-CoA, which participate in the extension and degradation of fatty acids. Thus, ACAA1 is an important regulator of lipid metabolism and plays an essential role in fatty acid oxidation and lipid metabolism. Our previous study findings revealed that ACAA1 is closely associated with the peroxisome proliferator-activated receptor (PPAR) signaling and fatty acid metabolism pathways, which are involved in fat deposition in sheep, leading to our hypothesis that ACAA1 may be involved in fat deposition by regulating lipid metabolism. However, the associated molecular mechanism remains unclear. In the present study, to assess the potential function of ACAA1 in sheep preadipocyte differentiation, we knocked down and overexpressed ACAA1 in sheep preadipocytes and evaluated the pattern of ACAA1 gene expression during preadipocyte differentiation by qRT-PCR. ACAA1 was significantly expressed in the early stage of adipocyte differentiation, and then its expression decreased. ACAA1 deficiency increased lipid accumulation and the triglyceride content and promoted sheep preadipocyte differentiation, whereas ACAA1 overexpression inhibited adipogenesis and decreased lipid accumulation and the triglyceride content. Simultaneously, we demonstrated that ACAA1 deficiency upregulated the expressions of the adipogenic marker genes PPARγ and C/EBPα in sheep preadipocytes, but ACAA1 overexpression inhibited the expressions of these markers, indicating that ACAA1 affects lipid metabolism by regulating adipogenic marker genes. Our results may promote a better understanding of the regulation of adipogenesis by ACAA1.

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Functional Comparison of High and Low Molecular Weight Chitosan on Lipid Metabolism and Signals in High-Fat Diet-Fed Rats

Marine Drugs ◽

10.3390/md16080251 ◽

2018 ◽

Vol 16 (8) ◽

pp. 251 ◽

Cited By ~ 13

Author(s):

Shing-Hwa Liu ◽

Chen-Yuan Chiu ◽

Ching-Ming Shi ◽

Meng-Tsan Chiang

Keyword(s):

Molecular Weight ◽

Lipid Metabolism ◽

Regulatory Element ◽

Lipid Absorption ◽

Liver Fat ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

High Fat ◽

Peroxisome Proliferator Activated Receptor ◽

Protein Expressions

The present study examined and compared the effects of low- and high-molecular weight (MW) chitosan, a nutraceutical, on lipid metabolism in the intestine and liver of high-fat (HF) diet-fed rats. High-MW chitosan as well as low-MW chitosan decreased liver weight, elongated the small intestine, improved the dysregulation of blood lipids and liver fat accumulation, and increased fecal lipid excretion in rats fed with HF diets. Supplementation of both high- and low-MW chitosan markedly inhibited the suppressed phosphorylated adenosine monophosphate (AMP)-activated protein kinase-α (AMPKα) and peroxisome proliferator-activated receptor-α (PPARα) protein expressions, and the increased lipogenesis/cholesterogenesis-associated protein expressions [peroxisome proliferator-activated receptor-γ (PPARγ), sterol regulatory element binding protein-1c and -2 (SREBP1c and SREBP2)] and the suppressed apolipoprotein E (ApoE) and microsomal triglyceride transfer protein (MTTP) protein expressions in the livers of rats fed with HF diets. Supplementation with both a low- and high-MW chitosan could also suppress the increased MTTP protein expression and the decreased angiopoietin-like protein-4 (Angptl4) expression in the intestines of rats fed with HF diets. In comparison between low- and high-MW chitosan, high-MW chitosan exhibits a higher efficiency than low-MW chitosan on the inhibition of intestinal lipid absorption and an increase of hepatic fatty acid oxidation, which can improve liver lipid biosynthesis and accumulation.

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