title: Counteracting roles of AMP deaminase and AMP kinase in the development of fatty liver.
abstract: Fatty liver (hepatic steatosis) is associated with nucleotide turnover, loss of ATP and generation of adenosine monophosphate (AMP). It is well known that in fatty liver, activity of the AMP-activated kinase (AMPK) is reduced and that its stimulation can prevent hepatic steatosis by both enhancing fat oxidation and reducing lipogenesis. Here we show that another AMP dependent enzyme, AMPD2, has opposing effects on fatty acid oxidation when compared to AMPK. In human hepatocytres, AMPD2 activation -either by overexpression or by lowering intracellular phosphate levels with fructose- is associated with a significant reduction in AMPK activity. Likewise, silencing of AMPK spontaneously increases AMPD activity, demonstrating that these enzymes counter-regulate each other. Furthermore, we show that a downstream product of AMP metabolism through AMPD2, uric acid, can inhibit AMPK activity in human hepatocytes. Finally, we show that fructose-induced fat accumulation in hepatocytes is due to a dominant stimulation of AMPD2 despite stimulating AMPK. In this regard, AMPD2-deficient hepatocytes demonstrate a further activation of AMPK after fructose exposure in association with increased fatty acid oxidation, and conversely silencing AMPK enhances AMPD-dependent fat accumulation. In vivo, we show that sucrose fed rats also develop fatty liver that is blocked by metformin in association with both a reduction in AMPD activity and an increase in AMPK activity. In summary, AMPD and AMPK are both important in hepatic fat accumulation and counter-regulate each other. We present the novel finding that uric acid inhibits AMPK kinase activity in fructose-fed hepatocytes thus providing new insights into the pathogenesis of fatty liver.
authors.affiliation: Division of Renal Diseases and Hypertension, University of Colorado-Denver, Aurora, Colorado, United States of America. miguel.lanaspagarcia@ucdenver.edu
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lanaspa
authors.forename: Christina
authors.initials: C
authors.lastname: Cicerchi
authors.forename: Gabriela
authors.initials: G
authors.lastname: Garcia
authors.forename: Nanxing
authors.initials: N
authors.lastname: Li
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Roncal-Jimenez
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rivard
authors.forename: Brandi
authors.initials: B
authors.lastname: Hunter
authors.forename: Ana
authors.initials: A
authors.lastname: Andrés-Hernando
authors.forename: Takuji
authors.initials: T
authors.lastname: Ishimoto
authors.forename: Laura G
authors.initials: LG
authors.lastname: Sánchez-Lozada
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Thomas
authors.forename: Robert S
authors.initials: RS
authors.lastname: Hodges
authors.forename: Colin T
authors.initials: CT
authors.lastname: Mant
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Johnson
mesh_terms: D000659:AMP Deaminase / Q000378:metabolism*; D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019748:Carbon-Carbon Double Bond Isomerases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005223:Fats / Q000378:metabolism; D005234:Fatty Liver / Q000201:enzymology / Q000378:metabolism*; D005632:Fructose / Q000378:metabolism / Q000494:pharmacology; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes; D008297:Male; D008687:Metformin / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D014527:Uric Acid / Q000378:metabolism
chemical_list: D005223:Fats; D007527:Isoenzymes; D014527:Uric Acid; D005632:Fructose; D008687:Metformin; D000263:Adenylate Kinase; D000659:AMP Deaminase; D019748:Carbon-Carbon Double Bond Isomerases; C085575:delta(3,5),delta(2,4)-dienoyl-CoA isomerase