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.
Highlights
There has been a progressive increase in obesity, type 2 diabetes, dyslipidemia and fatty liver throughout the world [1]
To determine whether the stimulation of fat oxidation by metformin is dependent on AMPK, we developed stable cell lines deficient in AMPK expression and observed that metformin was ineffective in increasing both enoyl CoA hydratase-1 (ECH1) expression, the phosphorylation of ACC at serine 79 and the levels of intracellular bhydroxybutyrate in AMPK-deficient cells (Fig. 1B and figure S1BC) indicating that AMPK controls fat oxidation by regulating ECH1 expression
We investigated the role of ECH1 in AMPK-dependent fat oxidation by generating cell lines where ECH1 was stably over-expressed (Fig. 1C, top)
Summary
There has been a progressive increase in obesity, type 2 diabetes, dyslipidemia and fatty liver throughout the world [1]. It is accepted that the inhibition of the energy sensor protein AMPK (AMP activated kinase) is an important step in the development of fatty liver [4,5,6]. AMPK activity is reduced in fatty liver and its inhibition is associated with fat accumulation. In this regard, AMPK modulates hepatic lipogenesis by multiple mechanisms including the phosphorylation (and inactivation) of transcription factors including SREBP-1c and -2 [7,8,9] and ChREBP [10] resulting in the inhibition of the transcription of lipogenic target genes FAS (fatty acid synthase), ACC1 (acetylCoA carboxylase) and SCD1 (stearoyl-CoA desaturase) [7,8,9]. While a reduction in AMPK activity is important in the development of hepatic steatosis, less is known about the mechanisms whereby AMPK activity is blocked in this condition
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