Peripheral effects of FAAH deficiency on fuel and energy homeostasis: Role of dysregulated lysine acetylation

Bhavapriya Vaitheesvaran, Li Yang, Kirsten Hartil, Sherrye Glaser, Stephen Yazulla, James E. Bruce, Irwin J. Kurland

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background: FAAH (fatty acid amide hydrolase), primarily expressed in the liver, hydrolyzes the endocannabinoids fatty acid ethanolamides (FAA). Human FAAH gene mutations are associated with increased body weight and obesity. In our present study, using targeted metabolite and lipid profiling, and new global acetylome profiling methodologies, we examined the role of the liver on fuel and energy homeostasis in whole body FAAH -/- mice. Methodology/Principal Findings: FAAH -/- mice exhibit altered energy homeostasis demonstrated by decreased oxygen consumption (Indirect calorimetry). FAAH -/- mice are hyperinsulinemic and have adipose, skeletal and hepatic insulin resistance as indicated by stable isotope phenotyping (SIPHEN). Fed state skeletal muscle and liver triglyceride levels was increased 2-3 fold, while glycogen was decreased 42% and 57% respectively. Hepatic cholesterol synthesis was decreased 22% in FAAH -/- mice. Dysregulated hepatic FAAH -/- lysine acetylation was consistent with their metabolite profiling. Fasted to fed increases in hepatic FAAH -/- acetyl-CoA (85%, p<0.01) corresponded to similar increases in citrate levels (45%). Altered FAAH -/- mitochondrial malate dehydrogenase (MDH2) acetylation, which can affect the malate aspartate shuttle, was consistent with our observation of a 25% decrease in fed malate and aspartate levels. Decreased fasted but not fed dihydroxyacetone-P and glycerol-3-P levels in FAAH -/- mice was consistent with a compensating contribution from decreased acetylation of fed FAAH -/- aldolase B. Fed FAAH -/- alcohol dehydrogenase (ADH) acetylation was also decreased. Conclusions/Significance: Whole body FAAH deletion contributes to a pre-diabetic phenotype by mechanisms resulting in impairment of hepatic glucose and lipid metabolism. FAAH -/- mice had altered hepatic lysine acetylation, the pattern sharing similarities with acetylation changes reported with chronic alcohol treatment. Dysregulated hepatic lysine acetylation seen with impaired FAA hydrolysis could support the liver's role in fostering the pre-diabetic state, and may reflect part of the mechanism underlying the hepatic effects of endocannabinoids in alcoholic liver disease mouse models.

Original languageEnglish (US)
Article numbere33717
JournalPLoS One
Volume7
Issue number3
DOIs
StatePublished - Mar 19 2012

Fingerprint

amide hydrolases
Acetylation
acetylation
Lysine
homeostasis
lysine
Homeostasis
fatty acids
energy
Liver
liver
mice
Endocannabinoids
Metabolites
fatty-acid amide hydrolase
Aspartic Acid
aspartic acid
malates
Fatty Acids
Dihydroxyacetone

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Peripheral effects of FAAH deficiency on fuel and energy homeostasis : Role of dysregulated lysine acetylation. / Vaitheesvaran, Bhavapriya; Yang, Li; Hartil, Kirsten; Glaser, Sherrye; Yazulla, Stephen; Bruce, James E.; Kurland, Irwin J.

In: PLoS One, Vol. 7, No. 3, e33717, 19.03.2012.

Research output: Contribution to journalArticle

Vaitheesvaran, Bhavapriya ; Yang, Li ; Hartil, Kirsten ; Glaser, Sherrye ; Yazulla, Stephen ; Bruce, James E. ; Kurland, Irwin J. / Peripheral effects of FAAH deficiency on fuel and energy homeostasis : Role of dysregulated lysine acetylation. In: PLoS One. 2012 ; Vol. 7, No. 3.
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abstract = "Background: FAAH (fatty acid amide hydrolase), primarily expressed in the liver, hydrolyzes the endocannabinoids fatty acid ethanolamides (FAA). Human FAAH gene mutations are associated with increased body weight and obesity. In our present study, using targeted metabolite and lipid profiling, and new global acetylome profiling methodologies, we examined the role of the liver on fuel and energy homeostasis in whole body FAAH -/- mice. Methodology/Principal Findings: FAAH -/- mice exhibit altered energy homeostasis demonstrated by decreased oxygen consumption (Indirect calorimetry). FAAH -/- mice are hyperinsulinemic and have adipose, skeletal and hepatic insulin resistance as indicated by stable isotope phenotyping (SIPHEN). Fed state skeletal muscle and liver triglyceride levels was increased 2-3 fold, while glycogen was decreased 42{\%} and 57{\%} respectively. Hepatic cholesterol synthesis was decreased 22{\%} in FAAH -/- mice. Dysregulated hepatic FAAH -/- lysine acetylation was consistent with their metabolite profiling. Fasted to fed increases in hepatic FAAH -/- acetyl-CoA (85{\%}, p<0.01) corresponded to similar increases in citrate levels (45{\%}). Altered FAAH -/- mitochondrial malate dehydrogenase (MDH2) acetylation, which can affect the malate aspartate shuttle, was consistent with our observation of a 25{\%} decrease in fed malate and aspartate levels. Decreased fasted but not fed dihydroxyacetone-P and glycerol-3-P levels in FAAH -/- mice was consistent with a compensating contribution from decreased acetylation of fed FAAH -/- aldolase B. Fed FAAH -/- alcohol dehydrogenase (ADH) acetylation was also decreased. Conclusions/Significance: Whole body FAAH deletion contributes to a pre-diabetic phenotype by mechanisms resulting in impairment of hepatic glucose and lipid metabolism. FAAH -/- mice had altered hepatic lysine acetylation, the pattern sharing similarities with acetylation changes reported with chronic alcohol treatment. Dysregulated hepatic lysine acetylation seen with impaired FAA hydrolysis could support the liver's role in fostering the pre-diabetic state, and may reflect part of the mechanism underlying the hepatic effects of endocannabinoids in alcoholic liver disease mouse models.",
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T2 - Role of dysregulated lysine acetylation

AU - Vaitheesvaran, Bhavapriya

AU - Yang, Li

AU - Hartil, Kirsten

AU - Glaser, Sherrye

AU - Yazulla, Stephen

AU - Bruce, James E.

AU - Kurland, Irwin J.

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N2 - Background: FAAH (fatty acid amide hydrolase), primarily expressed in the liver, hydrolyzes the endocannabinoids fatty acid ethanolamides (FAA). Human FAAH gene mutations are associated with increased body weight and obesity. In our present study, using targeted metabolite and lipid profiling, and new global acetylome profiling methodologies, we examined the role of the liver on fuel and energy homeostasis in whole body FAAH -/- mice. Methodology/Principal Findings: FAAH -/- mice exhibit altered energy homeostasis demonstrated by decreased oxygen consumption (Indirect calorimetry). FAAH -/- mice are hyperinsulinemic and have adipose, skeletal and hepatic insulin resistance as indicated by stable isotope phenotyping (SIPHEN). Fed state skeletal muscle and liver triglyceride levels was increased 2-3 fold, while glycogen was decreased 42% and 57% respectively. Hepatic cholesterol synthesis was decreased 22% in FAAH -/- mice. Dysregulated hepatic FAAH -/- lysine acetylation was consistent with their metabolite profiling. Fasted to fed increases in hepatic FAAH -/- acetyl-CoA (85%, p<0.01) corresponded to similar increases in citrate levels (45%). Altered FAAH -/- mitochondrial malate dehydrogenase (MDH2) acetylation, which can affect the malate aspartate shuttle, was consistent with our observation of a 25% decrease in fed malate and aspartate levels. Decreased fasted but not fed dihydroxyacetone-P and glycerol-3-P levels in FAAH -/- mice was consistent with a compensating contribution from decreased acetylation of fed FAAH -/- aldolase B. Fed FAAH -/- alcohol dehydrogenase (ADH) acetylation was also decreased. Conclusions/Significance: Whole body FAAH deletion contributes to a pre-diabetic phenotype by mechanisms resulting in impairment of hepatic glucose and lipid metabolism. FAAH -/- mice had altered hepatic lysine acetylation, the pattern sharing similarities with acetylation changes reported with chronic alcohol treatment. Dysregulated hepatic lysine acetylation seen with impaired FAA hydrolysis could support the liver's role in fostering the pre-diabetic state, and may reflect part of the mechanism underlying the hepatic effects of endocannabinoids in alcoholic liver disease mouse models.

AB - Background: FAAH (fatty acid amide hydrolase), primarily expressed in the liver, hydrolyzes the endocannabinoids fatty acid ethanolamides (FAA). Human FAAH gene mutations are associated with increased body weight and obesity. In our present study, using targeted metabolite and lipid profiling, and new global acetylome profiling methodologies, we examined the role of the liver on fuel and energy homeostasis in whole body FAAH -/- mice. Methodology/Principal Findings: FAAH -/- mice exhibit altered energy homeostasis demonstrated by decreased oxygen consumption (Indirect calorimetry). FAAH -/- mice are hyperinsulinemic and have adipose, skeletal and hepatic insulin resistance as indicated by stable isotope phenotyping (SIPHEN). Fed state skeletal muscle and liver triglyceride levels was increased 2-3 fold, while glycogen was decreased 42% and 57% respectively. Hepatic cholesterol synthesis was decreased 22% in FAAH -/- mice. Dysregulated hepatic FAAH -/- lysine acetylation was consistent with their metabolite profiling. Fasted to fed increases in hepatic FAAH -/- acetyl-CoA (85%, p<0.01) corresponded to similar increases in citrate levels (45%). Altered FAAH -/- mitochondrial malate dehydrogenase (MDH2) acetylation, which can affect the malate aspartate shuttle, was consistent with our observation of a 25% decrease in fed malate and aspartate levels. Decreased fasted but not fed dihydroxyacetone-P and glycerol-3-P levels in FAAH -/- mice was consistent with a compensating contribution from decreased acetylation of fed FAAH -/- aldolase B. Fed FAAH -/- alcohol dehydrogenase (ADH) acetylation was also decreased. Conclusions/Significance: Whole body FAAH deletion contributes to a pre-diabetic phenotype by mechanisms resulting in impairment of hepatic glucose and lipid metabolism. FAAH -/- mice had altered hepatic lysine acetylation, the pattern sharing similarities with acetylation changes reported with chronic alcohol treatment. Dysregulated hepatic lysine acetylation seen with impaired FAA hydrolysis could support the liver's role in fostering the pre-diabetic state, and may reflect part of the mechanism underlying the hepatic effects of endocannabinoids in alcoholic liver disease mouse models.

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