AMPK Re-Activation Suppresses Hepatic Steatosis but its Downregulation Does Not Promote Fatty Liver Development

Abstract

Nonalcoholic fatty liver disease is a highly prevalent component of disorders associated with disrupted energy homeostasis. Although dysregulation of the energy sensor AMP-activated protein kinase (AMPK) is viewed as a pathogenic factor in the development of fatty liver its role has not been directly demonstrated. Unexpectedly, we show here that liver-specific AMPK KO mice display normal hepatic lipid homeostasis and are not prone to fatty liver development, indicating that the decreases in AMPK activity associated with hepatic steatosis may be a consequence, rather than a cause, of changes in hepatic metabolism. In contrast, we found that pharmacological re-activation of downregulated AMPK in fatty liver is sufficient to normalize hepatic lipid content. Mechanistically, AMPK activation reduces hepatic triglyceride content both by inhibiting lipid synthesis and by stimulating fatty acid oxidation in an LKB1-dependent manner, through a transcription-independent mechanism. Furthermore, the effect of the antidiabetic drug metformin on lipogenesis inhibition and fatty acid oxidation stimulation was enhanced by combination treatment with small-molecule AMPK activators in primary hepatocytes from mice and humans. Overall, these results demonstrate that AMPK downregulation is not a triggering factor in fatty liver development but in contrast, establish the therapeutic impact of pharmacological AMPK re-activation in the treatment of fatty liver disease.

Glucose availability but not changes in pancreatic hormones sensitizes hepatic AMPK activity during nutritional transition in rodents

“…Although there is no clear evidence that polymorphisms in genes encoding AMPK subunits influence the occurrence of metabolic syndrome (26-28), a sustained decrease in AMPK activity has been found in the liver, skeletal muscle, and adipose tissue from obese or hyperglycemic rodents and humans in association with insulin resistance (29)(30)(31)(32)(33). Nevertheless, we have shown that liver-specific AMPK deficient mice display normal hepatic glucose and lipid homeostasis and are not prone to insulin resistance, suggesting that the decrease in AMPK activity associated with insulin resistance may be a consequence, rather than a cause, of changes in hepatic metabolism (10).…”

“…In the liver, AMPK plays a crucial role in the regulation of lipid partitioning between oxidative and biosynthetic pathways through the phosphorylation and inactivation of its well-established targets, acetyl-CoA carboxylase (ACC) 1/2 at Ser79/Ser212 residue and 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase (HMGCR) at Ser871 residue (8)(9)(10)(11)(12). The transition from the fasting to refed state is associated with modifications in hepatic lipid metabolism (i.e., increased fatty-acid synthesis and decreased fatty-acid oxidation) that appear to coincide with changes in the activation and phosphorylation of the AMPK !-subunit at Thr172 and ACC at Ser79 (13)(14)(15)(16).…”

Of mice and men: Is there a future for metformin in the treatment of hepatic steatosis?

“…58 More recent work has shown that metformin's ability to increase FAO (and inhibit lipogenesis) is enhanced when small-molecule AMPKspecific activators are used in combination with metformin in both rat and human primary hepatocytes. 59 These findings suggest that either (a) metformin does not robustly activate AMPK, or (b) metformin increases FAO independently of AMPK. Other studies have reported elevated gene expression of markers of FAO 60 and increased mitochondrial biogenesis in mice fed an HFD and treated with metformin, 28 which would potentially lead to greater oxidative capacity.…”

“…In primary rat hepatocytes, treatment with 0.5 mM metformin for 4 hours increased FAO (using 14 C‐oleate) and suppressed lipogenic gene expression via AMPK activation . More recent work has shown that metformin's ability to increase FAO (and inhibit lipogenesis) is enhanced when small‐molecule AMPK‐specific activators are used in combination with metformin in both rat and human primary hepatocytes . These findings suggest that either (a) metformin does not robustly activate AMPK, or (b) metformin increases FAO independently of AMPK.…”

The long‐term protective effects of neonatal administration of curcumin against nonalcoholic steatohepatitis in high‐fructose‐fed adolescent rats

“…It is important, however, to note that while the upregulation of AMPK protects against hepatic steatosis, its downregulation does not indicate susceptibility to hepatic steatosis (Boudaba et al. ).…”