A Model Construction of Starvation Induces Hepatic Steatosis and Transcriptome Analysis in Zebrafish Larvae

Hepatic steatosis caused by starvation, resulting in non-alcoholic fatty liver disease (NAFLD), has been a research topic of human clinical and animal experiments. To understand the molecular mechanisms underlying the triggering of abnormal liver metabolism by starvation, thus inducing hepatic lipid accumulation, we used zebrafish larvae to establish a starvation-induced hepatic steatosis model and conducted comparative transcriptome analysis by RNA-seq. We demonstrated that the incidence of larvae steatosis is positively correlated with starvation time. Under starvation conditions, the fatty acid transporter (slc27a2a and slc27a6-like) and fatty acid translocase (cd36) were up-regulated significantly to promote extrahepatic fatty acid uptake. Meanwhile, starvation inhibits the hepatic fatty acid metabolism pathway but activates the de novo lipogenesis pathway to a certain extent. More importantly, we detected that the expression of numerous apolipoprotein genes was downregulated and the secretion of very low density lipoprotein (VLDL) was inhibited significantly. These data suggest that starvation induces hepatic steatosis by promoting extrahepatic fatty acid uptake and lipogenesis, and inhibits hepatic fatty acid metabolism and lipid transport. Furthermore, we found that starvation-induced hepatic steatosis in zebrafish larvae can be rescued by targeting the knockout cd36 gene. In summary, these findings will help us understand the pathogenesis of starvation-induced NAFLD and provide important theoretical evidence that cd36 could serve as a potential target for the treatment of NAFLD.

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ETV5 regulates hepatic fatty acid metabolism through PPAR signaling pathway

10.2337/figshare.13102934.v1 ◽

2020 ◽

Author(s):

Ada Admin ◽

Zhuo Mao ◽

Mingji Feng ◽

Zhuoran Li ◽

Minsi Zhou ◽

...

Keyword(s):

Transcription Factor ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Association Studies ◽

Sequencing Analysis ◽

Dependent Manner ◽

Alcoholic Fatty Liver ◽

Hepatic Fatty Acid ◽

Ppar Signaling

ETV5 is an ETS transcription factor which has been associated with obesity in genomic association studies. However, little is known about the role of ETV5 in hepatic lipid metabolism and non-alcoholic fatty liver disease (NAFLD). In the present study, we found that ETV5 protein expression was increased in diet- and genetic-induced steatotic liver. ETV5 responded to the nutrient status in an mTORC1 dependent manner and in turn regulated mTORC1 activity. Both viral-mediated and genetic depletion of ETV5 in mice led to increased lipid accumulation in the liver. RNA sequencing analysis revealed that PPAR signaling and fatty acid degradation/metabolism pathways were significantly downregulated in ETV5 deficient hepatocytes in vivo and in vitro. Mechanistically, ETV5 could bind to the PPRE region of PPAR downstream genes and enhance its transactivity. Collectively, our study identifies ETV5 as a novel transcription factor for the regulation of hepatic fatty acid metabolism which is required for the optimal β oxidation process. ETV5 may provide a therapeutic target for the treatment of hepatic steatosis.

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Effect of hyperglycemia-hyperinsulinemia on whole body and regional fatty acid metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.276.3.e427 ◽

1999 ◽

Vol 276 (3) ◽

pp. E427-E434 ◽

Cited By ~ 10

Author(s):

Labros S. Sidossis ◽

Bettina Mittendorfer ◽

David Chinkes ◽

Eric Walser ◽

Robert R. Wolfe

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Fatty Acid Uptake ◽

Whole Body ◽

Acid Oxidation ◽

Acid Uptake ◽

Similar Extent ◽

Body Level

The effects of combined hyperglycemia-hyperinsulinemia on whole body, splanchnic, and leg fatty acid metabolism were determined in five volunteers. Catheters were placed in a femoral artery and vein and a hepatic vein. U-13C-labeled fatty acids were infused, once in the basal state and, on a different occasion, during infusion of dextrose (clamp; arterial glucose 8.8 ± 0.5 mmol/l). Lipids and heparin were infused together with the dextrose to maintain plasma fatty acid concentrations at basal levels. Fatty acid availability in plasma and fatty acid uptake across the splanchnic region and the leg were similar during the basal and clamp experiments. Dextrose infusion decreased fatty acid oxidation by 51.8% (whole body), 47.4% (splanchnic), and 64.3% (leg). Similarly, the percent fatty acid uptake oxidized decreased at the whole body level (53 to 29%), across the splanchnic region (30 to 13%), and in the leg (48 to 22%) during the clamp. We conclude that, in healthy men, combined hyperglycemia-hyperinsulinemia inhibits fatty acid oxidation to a similar extent at the whole body level, across the leg, and across the splanchnic region, even when fatty acid availability is constant.

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Transfection of L6 myoblasts with adipocyte fatty acid-binding protein cDNA does not affect fatty acid uptake but disturbs lipid metabolism and fusion

Biochemical Journal ◽

10.1042/bj3290265 ◽

1998 ◽

Vol 329 (2) ◽

pp. 265-273 ◽

Cited By ~ 21

Author(s):

F. M. Clemens PRINSEN ◽

H. Jacques VEERKAMP

Keyword(s):

Fatty Acid ◽

Fatty Acid Metabolism ◽

Fatty Acid Binding Protein ◽

Acid Metabolism ◽

Binding Protein ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

Fatty Acid Binding ◽

Transfected Cells ◽

Acid Binding Protein

We studied the involvement of fatty acid-binding protein (FABP) in growth, differentiation and fatty acid metabolism of muscle cells by lipofection of rat L6 myoblasts with rat heart (H) FABP cDNA or with rat adipocyte (A) FABP cDNA in a eukaryotic expression vector which contained a puromycin acetyltransferase cassette. Stable transfectants showed integration into the genome for all constructs and type-specific overexpression at the mRNA and protein level for the clones with H-FABP and A-FABP cDNA constructs. The rate of proliferation of myoblasts transfected with rat A-FABP cDNA was 2-fold higher compared with all other transfected cells. In addition, these myoblasts showed disturbed fusion and differentiation, as assessed by morphological examination and creatine kinase activity. Uptake rates of palmitate were equal for all clone types, in spite of different FABP content and composition. Palmitate oxidation over a 3 h period was similar in all clones from growth medium. After being cultured in differentiation medium, mock- and H-FABP-cDNA-transfected cells showed a lower fatty acid-oxidation rate, in contrast with A-FABP-cDNA-transfected clones. The ratio of [14C]palmitic acid incorporation into phosphatidylcholine and phosphatidylethanolamine of A-FABP-cDNA-transfected clones changed in the opposite direction in differentiation medium from that of mock- and H-FABP-cDNA-transfected clones. In conclusion, transfection of L6 myoblasts with A-FABP cDNA does not affect H-FABP content and fatty acid uptake, but changes fatty acid metabolism. The latter changes may be related to the observed fusion defect.

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ETV5 regulates hepatic fatty acid metabolism through PPAR signaling pathway

10.2337/figshare.13102934 ◽

2020 ◽

Author(s):

Ada Admin ◽

Zhuo Mao ◽

Mingji Feng ◽

Zhuoran Li ◽

Minsi Zhou ◽

...

Keyword(s):

Transcription Factor ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Association Studies ◽

Sequencing Analysis ◽

Dependent Manner ◽

Alcoholic Fatty Liver ◽

Hepatic Fatty Acid ◽

Ppar Signaling

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Regulation of fatty acid metabolism and gluconeogenesis by growth hormone and insulin in sheep hepatocyte cultures. Effects of lactation and pregnancy

Biochemical Journal ◽

10.1042/bj2740021 ◽

1991 ◽

Vol 274 (1) ◽

pp. 21-26 ◽

Cited By ~ 33

Author(s):

N Emmison ◽

L Agius ◽

V A Zammit

Keyword(s):

Growth Hormone ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Density Lipoprotein ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

Apparent Difference ◽

Exogenous Fatty Acid ◽

Hepatocyte Cultures

Primary monolayer hepatocyte cultures derived from non-mated, pregnant and lactating sheep were used to investigate the interactions between the effects of growth hormone and insulin on (i) the partitioning of fatty acid metabolism between oxidation and esterification, and (ii) the rate of gluconeogenesis. In hepatocytes from lactating sheep the rates of gluconeogenesis, ketogenesis and very-low-density lipoprotein secretion were approx. 2-fold higher than in cells from non-mated or pregnant animals. There was no apparent difference in the rates of fatty acid uptake between the three groups of sheep cells. Growth hormone stimulated gluconeogenesis only in hepatocytes from non-mated sheep. It has no effect on the flux of fatty acid towards ketone body formation. Growth hormone inhibited intracellular accumulation of acylglycerol from exogenous fatty acid. Insulin alone had no such effect, but it blunted the effect of growth hormone when the two hormones were present together. The data suggest that major differences may exist between ruminants and non-ruminants in the response of liver metabolism both to lactation per se and to the effects of growth hormone and insulin.

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Increased Fatty Acid Uptake and Altered Fatty Acid Metabolism in Insulin-Resistant Muscle of Obese Zucker Rats

Diabetes ◽

10.2337/diabetes.50.6.1389 ◽

2001 ◽

Vol 50 (6) ◽

pp. 1389-1396 ◽

Cited By ~ 70

Author(s):

Lorraine Patricia Turcotte ◽

Jason Richard Swenberger ◽

Michelle Zavitz Tucker ◽

Alice Jane Yee

Keyword(s):

Fatty Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Fatty Acid Uptake ◽

Zucker Rats ◽

Acid Uptake ◽

Insulin Resistant ◽

Obese Zucker Rats

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Zonation of hepatic fat accumulation: insights from mathematical modelling of nutrient gradients and fatty acid uptake

Journal of The Royal Society Interface ◽

10.1098/rsif.2017.0443 ◽

2017 ◽

Vol 14 (133) ◽

pp. 20170443 ◽

Cited By ~ 12

Author(s):

Jana Schleicher ◽

Uta Dahmen ◽

Reinhard Guthke ◽

Stefan Schuster

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Theoretical Perspective ◽

Fatty Acid Uptake ◽

Acid Uptake ◽

Maximal Velocity ◽

Uptake Mechanism ◽

Alcoholic Fatty Liver ◽

Hepatic Fatty Acid ◽

Triglyceride Accumulation

Intrinsic of non-alcoholic fatty liver diseases is an aberrant accumulation of triglycerides (steatosis), which occurs inhomogeneously within lobules. To improve our understanding of the mechanisms involved in this zonation patterning, we developed a mathematical multicompartment model of hepatic fatty acid metabolism accompanied by blood flow simulations. A model analysis determines the influence of the uptake process of fatty acids, the porto-central gradient of plasma fatty acid concentration, and the oxygen supply via blood on the zonation of triglyceride accumulation. From this theoretical perspective, the plasma oxygen gradient, but not the fatty acid gradient, leads the way to a zonated triglyceride accumulation by its decisive role in oxidative processes. In addition, the uptake mechanism of fatty acids seems to be fundamental for a pericentral dominance of steatosis. However, the mechanism of cellular fatty acid uptake from the blood is still under debate. Our theoretical approach supports the transporter-mediated uptake mechanism and reveals that the maximal velocity of fatty acid uptake affects the switching between a periportal and a pericentral triglyceride accumulation. Further research on hepatic fatty acid uptake is needed to push forward our understanding of aberrant triglyceride accumulation in diet-induced steatosis.

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