A Dicarboxylic Acid Derivative of the Hypolipidemic Peroxisome Proliferator, Tiadenol, Triggers Induction of Long-Chain Fatty Acid Metabolising Enzymes and Peroxisomal β-Oxidation

Background & Aims Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step of NAFLD. When combined with additional cellular stress, this benign status progresses to local and systemic pathological conditions such as NASH and insulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and other peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific Cpt1a knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism. Approach & Results Compared to the wild-type (WT) littermates, high fat diet (HFD)-fed LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress, inflammation and damage. Interestingly, increased energy expenditure was observed in LKO mice, accompanied by enhanced adipose tissue browning. RNAseq analysis revealed that the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis was activated in liver of LKO mice. Importantly, antibody-mediated neutralization of FGF21 abolished the healthier metabolic phenotype and adipose browning in LKO mice, indicating that the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice. Conclusions Liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.

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A single amino acid change humanizes long-chain fatty acid binding and activation of mouse peroxisome proliferator-activated receptor α

Journal of Molecular Graphics and Modelling ◽

10.1016/j.jmgm.2014.04.006 ◽

2014 ◽

Vol 51 ◽

pp. 27-36 ◽

Cited By ~ 4

Author(s):

Dhawal P. Oswal ◽

Gerald M. Alter ◽

S. Dean Rider ◽

Heather A. Hostetler

Keyword(s):

Fatty Acid ◽

Amino Acid Change ◽

Chain Fatty Acid ◽

Single Amino Acid ◽

Peroxisome Proliferator ◽

Long Chain Fatty Acid ◽

Peroxisome Proliferator Activated Receptor ◽

Fatty Acid Binding ◽

Single Amino Acid Change ◽

Long Chain

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Postprandial inhibition of gastric ghrelin secretion by long-chain fatty acid through GPR120 in isolated gastric ghrelin cells and mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00541.2011 ◽

2012 ◽

Vol 303 (3) ◽

pp. G367-G376 ◽

Cited By ~ 61

Author(s):

Xinping Lu ◽

Xilin Zhao ◽

Jianying Feng ◽

Alice P. Liou ◽

Shari Anthony ◽

...

Keyword(s):

Fatty Acid ◽

Gastric Mucosa ◽

Lipoprotein Lipase ◽

Chain Fatty Acid ◽

Peroxisome Proliferator ◽

Rt Pcr ◽

Long Chain Fatty Acid ◽

Peroxisome Proliferator Activated Receptor ◽

Ghrelin Secretion ◽

Long Chain

Ghrelin is a gastric peptide hormone that controls appetite and energy homeostasis. Plasma ghrelin levels rise before a meal and fall quickly thereafter. Elucidation of the regulation of ghrelin secretion has been hampered by the difficulty of directly interrogating ghrelin cells diffusely scattered within the complex gastric mucosa. Therefore, we generated transgenic mice with ghrelin cell expression of green fluorescent protein (GFP) to enable characterization of ghrelin secretion in a pure population of isolated gastric ghrelin-expressing GFP (Ghr-GFP) cells. Using quantitative RT-PCR and immunofluorescence staining, we detected a high level of expression of the long-chain fatty acid (LCFA) receptor GPR120, while the other LCFA receptor, GPR40, was undetectable. In short-term-cultured pure Ghr-GFP cells, the LCFAs docosadienoic acid, linolenic acid, and palmitoleic acid significantly suppressed ghrelin secretion. The physiological mechanism of LCFA inhibition on ghrelin secretion was studied in mice. Serum ghrelin levels were transiently suppressed after gastric gavage of LCFA-rich lipid in mice with pylorus ligation, indicating that the ghrelin cell may directly sense increased gastric LCFA derived from ingested intraluminal lipids. Meal-induced increase in gastric mucosal LCFA was assessed by measuring the transcripts of markers for tissue uptake of LCFA, lipoprotein lipase (LPL), fatty acid translocase (CD36), glycosylphosphatidylinositol-anchored HDL-binding protein 1, and nuclear fatty acid receptor peroxisome proliferator-activated receptor-γ. Quantitative RT-PCR studies indicate significantly increased mRNA levels of lipoprotein lipase, glycosylphosphatidylinositol-anchored HDL-binding protein 1, and peroxisome proliferator-activated receptor-γ in postprandial gastric mucosa. These results suggest that meal-related increases in gastric mucosal LCFA interact with GPR120 on ghrelin cells to inhibit ghrelin secretion.

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Investigation of protective effects of fatty acid binding protein 3 against long-chain fatty acid derivative-induced damage

10.3390/ecmc2020-07485 ◽

2020 ◽

Author(s):

Diana Zelencova ◽

Karlis Vilks ◽

Marina Makrecka-Kuka ◽

Edgars Liepinsh ◽

Kristaps Jaudzems

Keyword(s):

Fatty Acid ◽

Acid Derivative ◽

Fatty Acid Binding Protein ◽

Fatty Acid Derivative ◽

Chain Fatty Acid ◽

Protective Effects ◽

Long Chain Fatty Acid ◽

Fatty Acid Binding ◽

Acid Binding Protein ◽

Long Chain

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Confocal analysis of hepatocellular long-chain fatty acid uptake

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1995.269.6.g842 ◽

1995 ◽

Vol 269 (6) ◽

pp. G842-G851 ◽

Cited By ~ 2

Author(s):

C. Elsing ◽

U. Winn-Borner ◽

W. Stremmel

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Acid Derivative ◽

Fatty Acid Derivative ◽

Fatty Acid Uptake ◽

Chain Fatty Acid ◽

Acid Uptake ◽

Long Chain Fatty Acid ◽

Membrane Interaction ◽

Long Chain

Transmembrane transport and cytosolic accumulation of fatty acids were investigated using confocal laser scanning microscopy (cLSM). A Zeiss LSM 310 system was used to determine the uptake of the fluorescent fatty acid derivative 12-(N-methyl)-N-[(7-nitrobenz-2-oxa-1,3- diazol-4-yl)amino]octadecanoic acid (12-NBD stearate) (C18) in single rat hepatocytes. Uptake was a saturable process with a Michaelis-Menten constant value of 68 nM. Initial uptake velocity was dependent on extracellular presence of albumin and beta-lactoglobulin. Absence of albumin reduced uptake to 32 +/- 16% (P < 0.01) of control values. In the presence of unlabeled stearate, uptake of 12-NBD stearate was lowered to 49 +/- 12% (P < 0.01). Ion substitution experiments showed no sodium dependency of uptake. Increase in membrane potential led to a pronounced accumulation of the fatty acid derivative within the plasma membrane and in the adjacent cytoplasmic compartment, whereas membrane depolarization had no effect on uptake rates. In separate experiments line scans through representative hepatocytes were analyzed to generate "x-t" plots. 12-NBD stearate showed a fluorescence pattern with prominent staining of the area of the plasma membrane and the adjacent cytoplasm, dependent on the presence of extracellular albumin. For the hepatocellular cytosolic accumulation process of 12-NBD stearate a diffusion constant of 22.2 +/- 6.2 x 10(-9) cm2/s was calculated. In contrast to the long-chain fatty acid derivative 12-NBD stearate, short (C5)- and medium (C11)-chain fatty acids revealed no membrane interaction with hepatocytes. Erythrocytes also lacked a membrane interaction process for 12-NBD stearate. In conclusion, it was demonstrated that cLSM is capable of directly evaluating the cellular fatty acid uptake process at a subcellular level.

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Hepatic CPT1A Facilitates Liver-Adipose Cross-Talk via Induction of FGF21 in Mice

10.2337/figshare.16745977.v1 ◽

2021 ◽

Author(s):

Wei Sun ◽

Tao Nie ◽

Kuai Li ◽

Wenjie Wu ◽

Qiaoyun Long ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Chain Fatty Acid ◽

Metabolic Phenotype ◽

Fibroblast Growth Factor 21 ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Long Chain Fatty Acid ◽

Molecular Events ◽

Long Chain

Background & Aims Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step of NAFLD. When combined with additional cellular stress, this benign status progresses to local and systemic pathological conditions such as NASH and insulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and other peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific Cpt1a knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism. Approach & Results Compared to the wild-type (WT) littermates, high fat diet (HFD)-fed LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress, inflammation and damage. Interestingly, increased energy expenditure was observed in LKO mice, accompanied by enhanced adipose tissue browning. RNAseq analysis revealed that the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis was activated in liver of LKO mice. Importantly, antibody-mediated neutralization of FGF21 abolished the healthier metabolic phenotype and adipose browning in LKO mice, indicating that the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice. Conclusions Liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.

Download Full-text