JTP-103237, a monoacylglycerol acyltransferase inhibitor, prevents fatty liver and suppresses both triglyceride synthesis and de novo lipogenesis

5′AMP-activated protein kinase (AMPK) is known as metabolic sensor in mammalian cells that becomes activated by an increasing adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio. The heterotrimeric AMPK protein comprises three subunits, each of which has multiple phosphorylation sites, playing an important role in the regulation of essential molecular pathways. By phosphorylation of downstream proteins and modulation of gene transcription AMPK functions as a master switch of energy homeostasis in tissues with high metabolic turnover, such as the liver, skeletal muscle, and adipose tissue. Regulation of AMPK under conditions of chronic caloric oversupply emerged as substantial research target to get deeper insight into the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Evidence supporting the role of AMPK in NAFLD is mainly derived from preclinical cell culture and animal studies. Dysbalanced de novo lipogenesis has been identified as one of the key processes in NAFLD pathogenesis. Thus, the scope of this review is to provide an integrative overview of evidence, in particular from clinical studies and human samples, on the role of AMPK in the regulation of primarily de novo lipogenesis in human NAFLD.

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Concepts and Treatment Approaches in Nonalcoholic Fatty Liver Disease

Advances in Hepatology ◽

10.1155/2014/357965 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Dina L. Halegoua-De Marzio ◽

Jonathan M. Fenkel

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

De Novo ◽

Imaging Techniques ◽

De Novo Lipogenesis ◽

Central Adiposity ◽

Preventative Care ◽

Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) affects up to 30% of adults and is the most common liver disease in Western nations. NAFLD is associated with central adiposity, insulin resistance, type 2 diabetes mellitus, hyperlipidemia, and cardiovascular disease. It encompasses the entire spectrum of fatty liver diseases from simple steatosis to nonalcoholic steatohepatitis (NASH) with lobular/portal inflammation, hepatocellular necrosis, and fibrosis. Of those who develop NASH, 15–25% will progress to end stage liver disease and hepatocellular carcinoma over 10–20 years. Its pathogenesis is complex, and involves a state of lipid accumulation due to increased uptake of free fatty acids into the liver, impaired fatty acid beta oxidation, and increased incidence of de novo lipogenesis. Plasma aminotransferases and liver ultrasound are helpful in the diagnosis of NAFLD/NASH, but a liver biopsy is often required for definitive diagnosis. Many new plasma biomarkers and imaging techniques are now available that should improve the ability to diagnose NAFLD noninvasively Due to its complexity and extrahepatic complications, treatment of NAFLD requires a multidisciplinary approach with excellent preventative care, management, and treatment. This review will evaluate our current understanding of NAFLD, with a focus on existing therapeutic approaches and potential pharmacological developments.

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Effect of carbohydrate intake on de novo lipogenesis in human adipose tissue

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1987.253.6.e664 ◽

1987 ◽

Vol 253 (6) ◽

pp. E664-E669 ◽

Cited By ~ 5

Author(s):

C. Chascione ◽

D. H. Elwyn ◽

M. Davila ◽

K. M. Gil ◽

J. Askanazi ◽

...

Keyword(s):

Adipose Tissue ◽

De Novo ◽

Acid Synthesis ◽

De Novo Lipogenesis ◽

Whole Body ◽

High Intake ◽

Carbohydrate Diet ◽

Triglyceride Synthesis ◽

High Carbohydrate

Rates of synthesis, from [14C]glucose, of fatty acids (de novo lipogenesis) and glycerol (triglyceride synthesis) were measured in biopsies of adipose tissue from nutritionally depleted patients given low- or high-carbohydrate intravenous nutrition. Simultaneously, energy expenditure and whole-body lipogenesis were measured by indirect calorimetry. Rates of whole-body lipogenesis were zero on the low-carbohydrate diet and averaged 1.6 g.kg-1.day-1 on the high-carbohydrate diet. In vitro rates of triglyceride synthesis increased 3-fold going from the low to the high intake; rates of fatty acid synthesis increased approximately 80-fold. In vitro, lipogenesis accounted for less than 0.1% of triglyceride synthesis on the low intake and 4% on the high intake. On the high-carbohydrate intake, in vitro rates of triglyceride synthesis accounted for 61% of the rates of unidirectional triglyceride synthesis measured by indirect calorimetry. In vitro rates of lipogenesis accounted for 7% of whole-body lipogenesis. Discrepancies between in vitro rates of fatty acid synthesis from glucose, compared with acetate and citrate, as reported by others, suggest that in depleted patients on hypercaloric high-carbohydrate diets, adipose tissue may account for up to 40% of whole-body lipogenesis.

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Induction of fatty liver by Coleus forskohlii extract through enhancement of de novo triglyceride synthesis in mice

Toxicology Reports ◽

10.1016/j.toxrep.2014.09.013 ◽

2014 ◽

Vol 1 ◽

pp. 787-794 ◽

Cited By ~ 4

Author(s):

Keizo Umegaki ◽

Yuko Yamazaki ◽

Kaori Yokotani ◽

Tsuyoshi Chiba ◽

Yoko Sato ◽

...

Keyword(s):

Fatty Liver ◽

De Novo ◽

Coleus Forskohlii ◽

Triglyceride Synthesis

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Fatty Liver Due to Increased de novo Lipogenesis: Alterations in the Hepatic Peroxisomal Proteome

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2019.00248 ◽

2019 ◽

Vol 7 ◽

Cited By ~ 6

Author(s):

Birgit Knebel ◽

Pia Fahlbusch ◽

Matthias Dille ◽

Natalie Wahlers ◽

Sonja Hartwig ◽

...

Keyword(s):

Fatty Liver ◽

De Novo ◽

De Novo Lipogenesis

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A high-fat diet suppresses de novo lipogenesis and desaturation but not elongation and triglyceride synthesis in mice

The Journal of Lipid Research ◽

10.1194/jlr.m052308 ◽

2014 ◽

Vol 55 (12) ◽

pp. 2541-2553 ◽

Cited By ~ 78

Author(s):

Joao A. G. Duarte ◽

Filipa Carvalho ◽

Mackenzie Pearson ◽

Jay D. Horton ◽

Jeffrey D. Browning ◽

...

Keyword(s):

High Fat Diet ◽

De Novo ◽

De Novo Lipogenesis ◽

High Fat ◽

Triglyceride Synthesis

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Adiponectin: A Key Adipokine in Alcoholic Fatty Liver

Experimental Biology and Medicine ◽

10.3181/0902-mr-61 ◽

2009 ◽

Vol 234 (8) ◽

pp. 850-859 ◽

Cited By ~ 74

Author(s):

Min You ◽

Christopher Q. Rogers

Keyword(s):

Fatty Liver ◽

De Novo ◽

Regulatory System ◽

Receptor Expression ◽

Sirtuin 1 ◽

De Novo Lipogenesis ◽

Lipid Lowering ◽

Acid Oxidation ◽

Alcoholic Fatty Liver ◽

Central Target

Alcoholic fatty liver is a major risk factor for advanced liver injuries such as steatohepatitis, fibrosis, and cirrhosis. While the underlying mechanisms are multiple, the development of alcoholic fatty liver has been attributed to a combined increase in the rate of de novo lipogenesis and a decrease in the rate of fatty acid oxidation in animal liver. Among various transcriptional regulators, the hepatic SIRT1 (sirtuin 1)-AMPK (AMPK-activated kinase) signaling system represents a central target for the action of ethanol in the liver. Adiponectin is one of the adipocyte-derived adipokines with potent lipid-lowering properties. Growing evidence has demonstrated that the development of alcoholic fatty liver is associated with reduced circulating adiponectin levels, decreased hepatic adiponectin receptor expression, and impaired hepatic adiponectin signaling. Adiponectin confers protection against alcoholic fatty liver via modulation of complex hepatic signaling pathways largely controlled by the central regulatory system, SIRT1-AMPK axis. This review aims to integrate the current research findings of ethanol-mediated dysregulation of adiponectin and its receptors and to provide a comprehensive point of view for understanding the role of adiponectin signaling in the development of alcoholic fatty liver.

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Inhibition of matrix metalloproteinases increases PPAR-α and IL-6 and prevents dietary-induced hepatic steatosis and injury in a murine model

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00047.2006 ◽

2006 ◽

Vol 291 (6) ◽

pp. G1011-G1019 ◽

Cited By ~ 20

Author(s):

Ian P. J. Alwayn ◽

Charlotte Andersson ◽

Sang Lee ◽

Danielle A. Arsenault ◽

Bruce R. Bistrian ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Liver ◽

Hepatic Steatosis ◽

Essential Fatty Acid ◽

De Novo ◽

De Novo Lipogenesis ◽

Resonance Spectroscopy ◽

Liver Triglyceride ◽

Triglyceride Accumulation ◽

Tnf Α

Steatosis is a prominent feature of nonalcoholic fatty liver disease and a potential promoter of inflammation. Injury leading to cirrhosis is partly mediated by dysregulation of matrix protein turnover. Matrix metalloproteinase (MMP) inhibitors protect mice from lethal TNF-α induced liver injury. We hypothesized that Marimastat, a broad-spectrum MMP and TNF-α converting enzyme (TACE) inhibitor, might modulate this injury through interruption of inflammatory pathways. Triglyceride and phospholipid levels (liver, serum) and fatty acid profiles were used to assess essential fatty acid status and de novo lipogenesis as mechanisms for hepatic steatosis. Mice receiving a fat-free, high-carbohydrate diet (HCD) for 19 days developed severe fatty liver infiltration, demonstrated by histology, magnetic resonance spectroscopy, and elevated liver function tests. Animals receiving HCD plus Marimastat (HCD+MAR) were comparable to control animals. Increased tissue levels of peroxisome proliferator activated receptor-α (PPAR-α), higher levels of serum IL-6, and decreased levels of serum TNF-α receptor II were also seen in the HCD+MAR group compared with HCD-only. In addition, there was increased phosphorylation, and likely activation, of PPAR-α in the HCD+MAR group. PPAR-α is a transcription factor involved in β-oxidation of fatty acids, and IL-6 is a hepatoprotective cytokine. Liver triglyceride levels were higher and serum triglyceride and phospholipid levels lower with HCD-only but improved with Marimastat treatment. HCD-only and HCD+MAR groups were essential fatty acid deficient and had elevated rates of de novo lipogenesis. We therefore conclude that Marimastat reduces liver triglyceride accumulation by increasing fat oxidation and/or liver clearance of triglycerides. This may be related to increased expression and activation of PPAR-α or IL-6, respectively.

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