scholarly journals AMPK Activation Reduces Hepatic Lipid Content by Increasing Fat Oxidation In Vivo

2018 ◽  
Vol 19 (9) ◽  
pp. 2826 ◽  
Author(s):  
Marc Foretz ◽  
Patrick Even ◽  
Benoit Viollet
Keyword(s):  
Lipid Metabolism ◽  
De Novo ◽  
Fat Oxidation ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Ampk Activation ◽  
Hepatic Lipid ◽  
Adenoviral Delivery ◽  
Body Production

The energy sensor AMP-activated protein kinase (AMPK) is a key player in the control of energy metabolism. AMPK regulates hepatic lipid metabolism through the phosphorylation of its well-recognized downstream target acetyl CoA carboxylase (ACC). Although AMPK activation is proposed to lower hepatic triglyceride (TG) content via the inhibition of ACC to cause inhibition of de novo lipogenesis and stimulation of fatty acid oxidation (FAO), its contribution to the inhibition of FAO in vivo has been recently questioned. We generated a mouse model of AMPK activation specifically in the liver, achieved by expression of a constitutively active AMPK using adenoviral delivery. Indirect calorimetry studies revealed that liver-specific AMPK activation is sufficient to induce a reduction in the respiratory exchange ratio and an increase in FAO rates in vivo. This led to a more rapid metabolic switch from carbohydrate to lipid oxidation during the transition from fed to fasting. Finally, mice with chronic AMPK activation in the liver display high fat oxidation capacity evidenced by increased [C14]-palmitate oxidation and ketone body production leading to reduced hepatic TG content and body adiposity. Our findings suggest a role for hepatic AMPK in the remodeling of lipid metabolism between the liver and adipose tissue.

scholarly journals AMPK Activation Reduces Hepatic Lipid Content by Increasing Fat Oxidation in Vivo

2018 ◽  
Author(s):  
Marc Foretz ◽  
Patrick Even ◽  
Benoit Viollet
Keyword(s):  
Lipid Metabolism ◽  
De Novo ◽  
Fat Oxidation ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Ampk Activation ◽  
Hepatic Lipid ◽  
Adenoviral Delivery ◽  
Body Production

The energy sensor AMP-activated protein kinase (AMPK) is a key player in the control of energy metabolism. AMPK regulates hepatic lipid metabolism through the phosphorylation of its well-recognized downstream target acetyl CoA carboxylase (ACC). Although AMPK activation is proposed to lower hepatic triglyceride (TG) content via the inhibition of ACC to cause inhibition of de novo lipogenesis and stimulation of fatty acid oxidation (FAO), its contribution to the inhibition of FAO in vivo has been recently questioned. We generated a mouse model of AMPK activation specifically in the liver achieved by expression of a constitutively active AMPK using adenoviral delivery. Indirect calorimetry studies revealed that liver-specific AMPK activation is sufficient to induce a reduction in the respiratory exchange ratio and an increase in FAO rates in vivo. This led to a more rapid metabolic switch from carbohydrate to lipid oxidation during the transition from fed to fasting. Finally, mice with chronic AMPK activation in the liver display high fat oxidation capacity evidenced by increased [C14]-palmitate oxidation and ketone body production leading to reduced hepatic TG content and body adiposity. Our findings suggest a role for hepatic AMPK in the remodeling of lipid metabolism between the liver and adipose tissue.

scholarly journals Fructose-enriched diet affects hepatic lipid metabolism in young male and female rats in different ways

2019 ◽  
Vol 71 (3) ◽  
pp. 417-424 ◽  
Author(s):  
Jelena Brkljacic ◽  
Natasa Velickovic ◽  
Ivana Elakovic ◽  
Ana Teofilovic ◽  
Danijela Vojnovic-Milutinovic ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Female Rats ◽  
Acid Oxidation ◽  
Hepatic Lipid Metabolism ◽  
Male And Female ◽  
Hepatic Lipid ◽  
Male And Female Rats ◽  
Dietary Fructose

An increase in fructose consumption coincides with a rising incidence of metabolic disorders. Dietary fructose has been shown to affect hepatic lipid metabolism in a way that may lead to lipid deposition in the liver. In this study, we tested the hypothesis that the effects of fructose overconsumption on hepatic lipid metabolism differ between sexes. To that end we examined the effects of a high-fructose diet on the expression of key enzymes and transcription factors involved in the regulation of fatty acid oxidation and de novo lipogenesis in the liver of 12-week-old male and female Wistar rats. Immediately after weaning, the rats were subjected to a standard diet and 10% fructose solution or drinking water for 9 weeks. The fructose-enriched diet induced hypertriglyceridemia and increased hepatic de novo lipogenesis in both sexes, without lipid deposition in the liver. At the same time, visceral adiposity was observed only in female rats, while in males the treatment stimulated hepatic fatty acid oxidation. The fructose-enriched diet induced sex-specific effects on hepatic lipid metabolism in young rats. These results imply that male and female rats employ different strategies to cope with dietary fructose-related energy overload and to avoid lipid accumulation in the liver. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III41009]

scholarly journals CTRP9 transgenic mice are protected from diet-induced obesity and metabolic dysfunction

2013 ◽  
Vol 305 (5) ◽  
pp. R522-R533 ◽  
Author(s):  
Jonathan M. Peterson ◽  
Zhikui Wei ◽  
Marcus M. Seldin ◽  
Mardi S. Byerly ◽  
Susan Aja ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Transgenic Mice ◽  
High Fat Diet ◽  
Fat Oxidation ◽  
Acid Oxidation ◽  
Ampk Activation ◽  
High Fat ◽  
Diet Induced Obesity

CTRP9 is a secreted multimeric protein of the C1q family and the closest paralog of the insulin-sensitizing adipokine, adiponectin. The metabolic function of this adipose tissue-derived plasma protein remains largely unknown. Here, we show that the circulating levels of CTRP9 are downregulated in diet-induced obese mice and upregulated upon refeeding. Overexpressing CTRP9 resulted in lean mice that dramatically resisted weight gain induced by a high-fat diet, largely through decreased food intake and increased basal metabolism. Enhanced fat oxidation in CTRP9 transgenic mice resulted from increases in skeletal muscle mitochondrial content, expression of enzymes involved in fatty acid oxidation (LCAD and MCAD), and chronic AMPK activation. Hepatic and skeletal muscle triglyceride levels were substantially decreased in transgenic mice. Consequently, CTRP9 transgenic mice had a greatly improved metabolic profile with markedly reduced fasting insulin and glucose levels. The high-fat diet-induced obesity, insulin resistance, and hepatic steatosis observed in wild-type mice were prevented in transgenic mice. Consistent with the in vivo data, recombinant protein significantly enhanced fat oxidation in L6 myotubes via AMPK activation and reduced lipid accumulation in H4IIE hepatocytes. Collectively, these data establish CTRP9 as a novel metabolic regulator and a new component of the metabolic network that links adipose tissue to lipid metabolism in skeletal muscle and liver.

scholarly journals CDKN2A/p16INK4a suppresses hepatic fatty acid oxidation through the AMPKα2-SIRT1-PPARα signaling pathway

2020 ◽  
Vol 295 (50) ◽  
pp. 17310-17322
Author(s):  
Yann Deleye ◽  
Alexia Karen Cotte ◽  
Sarah Anissa Hannou ◽  
Nathalie Hennuyer ◽  
Lucie Bernard ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Oxidation ◽  
Lipid Droplet ◽  
Acid Oxidation ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Lipid ◽  
Hepatic Fatty Acid Oxidation

In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near CDKN2A, the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of in vivo and in vitro approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, p16 overexpression was associated with triglyceride accumulation and increased lipid droplet numbers in vitro, and decreased ketogenesis and hepatic mitochondrial activity in vivo. Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between CDKN2A expression and PPARA and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.

scholarly journals Effect of Central Corticotropin-Releasing Factor on Hepatic Lipid Metabolism and Inflammation-Related Gene Expression in Rats

2021 ◽  
Vol 22 (8) ◽  
pp. 3940
Author(s):  
Yukiomi Nakade ◽  
Rena Kitano ◽  
Taeko Yamauchi ◽  
Satoshi Kimoto ◽  
Kazumasa Sakamoto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
De Novo ◽  
Corticotropin Releasing Factor ◽  
De Novo Lipogenesis ◽  
Control Group ◽  
Mrna Levels ◽  
Related Gene ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Lipid

Corticotropin-releasing factor (CRF) in the brain acts on physiological and pathophysiological modulation of the hepatobiliary system. Central CRF administration aggravates experimental acute liver injury by decreasing hepatic blood flow. Conversely, minimal evidence is available regarding the effect of centrally acting CRF on hepatic lipid metabolism and inflammation. We examined whether central CRF affects hepatic lipid metabolism and inflammation-related gene expression in rats. Male Long Evans rats were intracisternally injected with CRF (10 μg) or saline. Rats were sacrificed 2 h, 6 h, and 24 h after the CRF injection, the liver was isolated, and mRNA was extracted. Next, hepatic lipid metabolism and inflammation-related gene expression were examined. Hepatic SREBF1 (sterol regulatory element-binding transcription factor 1) mRNA levels were significantly increased 6 h and 24 h after intracisternal CRF administration when compared with those in the control group. Hepatic TNFα and IL1β mRNA levels increased significantly 6 h after intracisternal CRF administration. Hepatic sympathectomy or guanethidine treatment, not hepatic branch vagotomy or atropine treatment, inhibited central CRF-induced increase in hepatic SREBF1, TNFα and IL1β mRNA levels. These results indicated that central CRF affects hepatic de novo lipogenesis and inflammation-related gene expression through the sympathetic-noradrenergic nervous system in rats.

scholarly journals DHT causes liver steatosis via transcriptional regulation of SCAP in normal weight female mice

2021 ◽  
Author(s):  
Tina Seidu ◽  
Patrick McWhorter ◽  
Jessie Myer ◽  
Rabita Alamgir ◽  
Nicole Eregha ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Protein Expression ◽  
Low Dose ◽  
De Novo ◽  
Polycystic Ovary ◽  
Liver Steatosis ◽  
Normal Weight ◽  
De Novo Lipogenesis ◽  
Hepatic Lipid ◽  
Female Mice

Hyperandrogenemia (HA) is a hallmark of polycystic ovary syndrome (PCOS) and is an integral element of nonalcoholic fatty liver disease (NALFD) in females. Administering low dose dihydrotestosterone (DHT) induced a normal weight PCOS-like female mouse model displaying NAFLD. The molecular mechanism of HA-induced NAFLD has not been fully determined. We hypothesized that DHT would regulate hepatic lipid metabolism via increased SREBP1 expression leading to NAFLD. We extracted liver from control and low dose DHT female mice; and performed histological and biochemical lipid pro-files, Western blot, immunoprecipitation, chromatin immunoprecipitation, and real-time quantitative PCR analyses. DHT lowered the 65 kD form of cytosolic SREBP1 in the liver compared to controls. However, DHT did not alter the levels of SREBP2 in the liver. DHT mice displayed increased SCAP protein expression and SCAP-SREBP1 binding compared to controls. DHT mice exhibited increased AR binding to intron-8 of SCAP leading to increased SCAP mRNA compared to controls. FAS mRNA and protein expression was increased in liver of DHT mice compared to controls. p-ACC levels were unaltered in liver. Other lipid metabolism pathways were examined in liver, but no changes were observed. Our findings support evidence that DHT increased de novo lipogenic proteins resulting in increased hepatic lipid content via regulation of SREBP1 in liver. We show that in the presence of DHT the SCAP-SREBP1 interaction was elevated leading to increased nuclear SREBP1 resulting in increased de novo lipogenesis. We propose that the mechanism of action may be increased AR binding to an ARE in SCAP intron-8.

scholarly journals Alcohol effects on hepatic lipid metabolism

2020 ◽  
Vol 61 (4) ◽  
pp. 470-479 ◽  
Author(s):  
Sookyoung Jeon ◽  
Rotonya Carr
Keyword(s):  
Lipid Metabolism ◽  
Liver Disease ◽  
Hepatic Steatosis ◽  
De Novo ◽  
Lipid Synthesis ◽  
Acid Oxidation ◽  
Lipid Uptake ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Lipid ◽  
Hepatic Lipid Accumulation

Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease with significant morbidity and mortality worldwide. ALD begins with simple hepatic steatosis and progresses to alcoholic steatohepatitis, fibrosis, and cirrhosis. The severity of hepatic steatosis is highly associated with the development of later stages of ALD. This review explores the disturbances of alcohol-induced hepatic lipid metabolism through altered hepatic lipid uptake, de novo lipid synthesis, fatty acid oxidation, hepatic lipid export, and lipid droplet formation and catabolism. In addition, we review emerging data on the contributions of genetics and bioactive lipid metabolism in alcohol-induced hepatic lipid accumulation.

scholarly journals A nutrient cocktail prevents lipid metabolism alterations induced by 20 days of daily steps reduction and fructose overfeeding: result from a randomized study

2019 ◽  
Vol 126 (1) ◽  
pp. 88-101 ◽  
Author(s):  
Anthony Damiot ◽  
Rémi Demangel ◽  
John Noone ◽  
Isabelle Chery ◽  
Alexandre Zahariev ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Physical Inactivity ◽  
De Novo ◽  
Fat Oxidation ◽  
De Novo Lipogenesis ◽  
Sedentary Behaviors ◽  
Protein Ubiquitination ◽  
Total Fat

Physical inactivity and sedentary behaviors are independent risk factors for numerous diseases. We examined the ability of a nutrient cocktail composed of polyphenols, omega-3 fatty acids, vitamin E, and selenium to prevent the expected metabolic alterations induced by physical inactivity and sedentary behaviors. Healthy trained men ( n = 20) (averaging ∼14,000 steps/day and engaged in sports) were randomly divided into a control group (no supplementation) and a cocktail group for a 20-day free-living intervention during which they stopped exercise and decreased their daily steps (averaging ∼3,000 steps/day). During the last 10 days, metabolic changes were further triggered by fructose overfeeding. On days 0, 10, and 20, body composition (dual energy X-ray), blood chemistry, glucose tolerance [oral glucose tolerance test (OGTT)], and substrate oxidation (indirect calorimetry) were measured. OGTT included 1% fructose labeled with (U-13C) fructose to assess liver de novo lipogenesis. Histological changes and related cellular markers were assessed from muscle biopsies collected on days 0 and 20. While the cocktail did not prevent the decrease in insulin sensitivity and its muscular correlates induced by the intervention, it fully prevented the hypertriglyceridemia, the drop in fasting HDL and total fat oxidation, and the increase in de novo lipogenesis. The cocktail further prevented the decrease in the type-IIa muscle fiber cross-sectional area and was associated with lower protein ubiquitination content. The circulating antioxidant capacity was improved by the cocktail following the OGTT. In conclusion, a cocktail of nutrient compounds from dietary origin protects against the alterations in lipid metabolism induced by physical inactivity and fructose overfeeding. NEW & NOTEWORTHY This is the first study to test the efficacy of a novel dietary nutrient cocktail on the metabolic and physiological changes occurring during 20 days of physical inactivity along with fructose overfeeding. The main findings of this study are that 1) reduction in daily steps leads to decreased insulin sensitivity and total fat oxidation, resulting in hyperlipemia and increased de novo lipogenesis and 2) a cocktail supplement prevents the alterations on lipid metabolism.

scholarly journals Anti-Obesity Effects of Microalgae

2019 ◽  
Vol 21 (1) ◽  
pp. 41 ◽  
Author(s):  
Saioa Gómez-Zorita ◽  
Jenifer Trepiana ◽  
Maitane González-Arceo ◽  
Leixuri Aguirre ◽  
Iñaki Milton-Laskibar ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
In Vivo Studies ◽  
Acid Oxidation ◽  
Low Grade ◽  
Food Ingredients ◽  
Brown Adipose

In recent years, microalgae have attracted great interest for their potential applications in nutraceutical and pharmaceutical industry as an interesting source of bioactive medicinal products and food ingredients with anti-oxidant, anti-inflammatory, anti-cancer, and anti-microbial properties. One potential application for bioactive microalgae compounds is obesity treatment. This review gathers together in vitro and in vivo studies which address the anti-obesity effects of microalgae extracts. The scientific literature supplies evidence supporting an anti-obesity effect of several microalgae: Euglena gracilis, Phaeodactylum tricornutum, Spirulina maxima, Spirulina platensis, or Nitzschia laevis. Regarding the mechanisms of action, microalgae can inhibit pre-adipocyte differentiation and reduce de novo lipogenesis and triglyceride (TG) assembly, thus limiting TG accumulation. Increased lipolysis and fatty acid oxidation can also be observed. Finally, microalgae can induce increased energy expenditure via thermogenesis activation in brown adipose tissue, and browning in white adipose tissue. Along with the reduction in body fat accumulation, other hallmarks of individuals with obesity, such as enhanced plasma lipid levels, insulin resistance, diabetes, or systemic low-grade inflammation are also improved by microalgae treatment. Not only the anti-obesity effect of microalgae but also the improvement of several comorbidities, previously observed in preclinical studies, has been confirmed in clinical trials.

scholarly journals ULK1 Regulates Hepatic Lipid Metabolism via Autophagy Independent Mechanisms

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A303-A303
Author(s):  
Young Do Koo ◽  
Romilia Tatiana Castillo ◽  
Antentor Othrell Hinton ◽  
Evan Dale Abel
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Chow Diet ◽  
Hepatic Lipid Metabolism ◽  
Critical Pathway ◽  
Hepatic Lipid ◽  
Normal Chow

Abstract Non-alcoholic steatohepatitis (NASH), a major complication of obesity, diabetes, and metabolic syndrome has emerged as a leading cause of chronic liver disease and a risk factor for hepatocellular carcinoma. Autophagy is a critical pathway for the degradation of intracellular components by lysosomes. Established functions for autophagy in hepatic lipid metabolism and insulin sensitivity suggest a mechanistic link between altered autophagy and NASH. However, the interactions between insulin sensitivity, NASH, and autophagy are incompletely understood. The Unc-51 Like Autophagy Activating Kinase 1 (ULK1) is the only serine/threonine kinase in the core autophagy pathway and thus represents an excellent drug target. In this study, we observed that ULK1 may directly regulate insulin signaling and lipid metabolism via mechanisms that might involve modulation of AKT dephosphorylation. Surprisingly, silencing ULK1 did not significantly alter autophagy in hepatocytes despite impairing insulin-stimulated activation of AKT. To further elucidate the autophagy-independent role of ULK1 in hepatic lipid metabolism and insulin action, ULK1 liver-specific knock-out mice were generated. L-ULK1 KO mice exhibited impaired glucose tolerance and insulin resistance on a normal chow diet or 60% high-fat diet (HFD). In young mice (4 weeks after birth), the expression of genes that regulate de novo lipogenesis, such as FAS, SCD1, and SREBP1-c were induced in livers of L-ULK1KO mice even prior to the development of insulin resistance and obesity. Hepatomegaly and lipid accumulation developed in L-ULK1KO on normal chow and was exacerbated relative to wild type mice on a HFD. Serum concentrations of insulin, triglyceride, cholesterol, AST and ALT were significantly increased. In contrast, L-ULK2 KO mice were phenotypically normal. To identify putative novel ULK1 targets, we conducted a phospho-proteomics screen in a ULK1 deficient hepatocyte cell line. We identified a relatively small number of novel proteins whose phosphorylation levels were reduced by ULK1 deficiency. The identification of these targets supports autophagy-independent mechanisms of action of ULK1. Recently, we confirmed that NCOA3, one of the targets regulates hepatic lipid metabolism by interacting directly with ULK1. These data suggest that ULK-1 may regulate cellular targets that regulate hepatic lipid metabolism and insulin sensitivity.

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