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

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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De novo and recurrence of metabolic dysfunction-associated fatty liver disease after liver transplantation

World Journal of Hepatology ◽

10.4254/wjh.v13.i12.1991 ◽

2021 ◽

Vol 13 (12) ◽

pp. 1991-2004

Author(s):

Ma Ai Thanda Han ◽

Raquel Olivo ◽

Catherine J Choi ◽

Nikolaos Pyrsopoulos

Keyword(s):

Liver Transplantation ◽

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

De Novo ◽

Metabolic Dysfunction

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Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease

10.2337/figshare.13150568 ◽

2020 ◽

Author(s):

Kasper W. ter Horst ◽

Daniel F. Vatner ◽

Dongyan Zhang ◽

Gary W. Cline ◽

Mariette T. Ackermans ◽

...

Keyword(s):

Insulin Resistance ◽

Bariatric Surgery ◽

Liver Disease ◽

Fatty Liver ◽

Insulin Signaling ◽

Fatty Liver Disease ◽

De Novo ◽

Glucose Production ◽

Hepatic Insulin Resistance ◽

Alcoholic Fatty Liver

Objective: Both glucose and triglyceride production are increased in Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). For decades, the leading hypothesis to explain these paradoxical observations has been selective hepatic insulin resistance, wherein insulin drives de novo lipogenesis (DNL), while failing to suppress glucose production. Here, we aimed to test this hypothesis in humans. Research Design and Methods: We recruited obese subjects who met criteria for bariatric surgery with (n=16) or without (n=15) NAFLD and assessed: i) insulin-mediated regulation of hepatic and peripheral glucose metabolism using hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose, ii) fasting and carbohydrate-driven hepatic DNL using deuterated water (2H2O), and iii) hepatocellular insulin signaling in liver biopsies collected during bariatric surgery. Results: As compared with subjects without NAFLD, subjects with NAFLD demonstrated impaired insulin-mediated suppression of glucose production and attenuated -not increased- glucose-stimulated/high-insulin lipogenesis. Fructose-stimulated/low-insulin lipogenesis was intact. Hepatocellular insulin signaling, assessed for the first time in humans, exhibited a proximal block in insulin-resistant subjects: signaling was attenuated from the level of the insulin receptor through both glucose and lipogenesis pathways. The carbohydrate-regulated lipogenic transcription factor ChREBP was increased in subjects with NAFLD. Conclusions: Acute increases in lipogenesis in humans with NAFLD are not explained by altered molecular regulation of lipogenesis through a paradoxical increase in lipogenic insulin action; rather, increases in lipogenic substrate availability may be the key. <a></a>

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Time Course of the Development of Nonalcoholic Fatty Liver Disease in the Otsuka Long-Evans Tokushima Fatty Rat

Gastroenterology Research and Practice ◽

10.1155/2013/342648 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 13

Author(s):

Yi-Sun Song ◽

Cheng-Hu Fang ◽

Byung-Im So ◽

Jun-Young Park ◽

Yonggu Lee ◽

...

Keyword(s):

Gene Expression ◽

Liver Disease ◽

Animal Models ◽

Fatty Liver ◽

Fatty Liver Disease ◽

De Novo ◽

Histological Changes ◽

Nonalcoholic Fatty Liver ◽

Oletf Rats ◽

Long Evans

Nonalcoholic fatty liver disease (NAFLD) is considered a hepatic manifestation of metabolic syndrome. In this study, we investigated histological and biochemical changes in NAFLD and the gene expression involvingde novolipogenesis in Otsuka Long-Evans Tokushima fatty (OLETF) rats. We used OLETF rats and Long-Evans Tokushima Otsuka (LETO) rats as animal models of NAFLD and as controls, respectively. Consistent observations were made at 4-week intervals up to 50 weeks of age, and all rats were fed ad libitum with standard food. Biochemical and histological changes were observed, and gene expression involved inde novolipogenesis was measured using real-time polymerase chain reactions. As a results hepatic micro- and macrovesicular steatosis and hepatocyte ballooning were evident in the OLETF rats at 22–38 weeks of age but disappeared after 42 weeks; no fibrosis or collagen deposition was observed. Gene expression involved inde novolipogenesis followed a pattern similar to that of the histological changes. In conclusion, in the absence of dietary manipulation, hepatic steatosis in OLETF rats is evident at 22–38 weeks and declines after 42 weeks. Therefore, OLETF rats at 22–38 weeks are recommended as animal models of hepatic steatosis.

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