A Narrative Review on the Role of AMPK on De Novo Lipogenesis in Non-Alcoholic Fatty Liver Disease: Evidence from Human Studies

Abstract

5′AMP-activated protein kinase (AMPK) is known as metabolic sensor in mammalian cells that becomes activated by an increasing adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio. The heterotrimeric AMPK protein comprises three subunits, each of which has multiple phosphorylation sites, playing an important role in the regulation of essential molecular pathways. By phosphorylation of downstream proteins and modulation of gene transcription AMPK functions as a master switch of energy homeostasis in tissues with high metabolic turnover, such as the liver, skeletal muscle, and adipose tissue. Regulation of AMPK under conditions of chronic caloric oversupply emerged as substantial research target to get deeper insight into the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Evidence supporting the role of AMPK in NAFLD is mainly derived from preclinical cell culture and animal studies. Dysbalanced de novo lipogenesis has been identified as one of the key processes in NAFLD pathogenesis. Thus, the scope of this review is to provide an integrative overview of evidence, in particular from clinical studies and human samples, on the role of AMPK in the regulation of primarily de novo lipogenesis in human NAFLD.

The Role of Physical Activity in Nonalcoholic and Metabolic Dysfunction Associated Fatty Liver Disease

“…IR is the early pathophysiologic trigger event in the overnutrition-MeSy-T2D spectrum ([ 43 ]; reviewed in [ 44 ]). IR is closely related to ectopic lipid deposition, whereby liver fat is recognized as central predictor of whole-body insulin sensitivity, or reciprocally IR under human in vivo conditions [ 4 , 43 , 44 , 45 , 46 ].…”

“…IR is the early pathophysiologic trigger event in the overnutrition-MeSy-T2D spectrum ([ 43 ]; reviewed in [ 44 ]). IR is closely related to ectopic lipid deposition, whereby liver fat is recognized as central predictor of whole-body insulin sensitivity, or reciprocally IR under human in vivo conditions [ 4 , 43 , 44 , 45 , 46 ]. The metabolic condition of skeletal muscle, the organ system most evidently impacted by physical exercise, was recently found to be influenced by liver lipid status in a dose dependent fashion [ 46 ].…”

“…Hallmarks of peripheral IR are impaired glucose transporter 4 (GLUT4) mediated glucose uptake by skeletal muscle, and compromised suppressibility of WAT lipolysis (reviewed in [ 44 ]). Visceral obesity is common in IR subjects and extensive evidence implicates that elevated circulating non-esterified fatty acids (NEFA) from inappropriate WAT hyperlipolysis are contributing to the etiology [ 17 , 70 , 71 ].…”

“…This maneuver, which is associated with higher mitochondrial capacity of the exercised muscle, represents a unique example of metabolic flexibility [ 54 ]. As regards NAFLD/MAFLD, improved glycogen storage and mobilization capacity would be desirable, since this would theoretically help to relieve glucose load from the liver and thereby leave less substrate for de novo lipogenesis (reviewed in [ 44 ]). Remarkably, a single bout of exercise can substantially rise insulin sensitivity in IR subjects, while the subsequent increase in insulin stimulated skeletal muscle glucose uptake and glycogen synthesis can be observed for up to 48 h. Interestingly, glycogen levels are increased independently from muscle glycogen content under such conditions (reviewed in [ 96 ]).…”

“…Physical exercise basically modulates supply of substrates and signaling molecules (via enhanced capillary perfusion, capillary recruitment/expansion of capillary volume); membrane transport of glucose (effects are majorly reported for GLUT4); mitochondrial adaptations (mitochondrial plasticity) and metabolic activation (glycolysis, lipid metabolism); and storage capacity and mobilization of energetic substrates (glycogen, IMCL). Effects of physical activity on insulin action and glucose uptake mediated by activation of AMP-activated protein kinase have been evaluated in various clinical settings (reviewed in [44]). AKT2, gene 2 encoding proteinkinase B; AMPK, AMP-activated protein kinase; CaMK, calcium/calmodulin kinase; DAG, diacylglycerol; FATP, fatty acid transport protein; G6P, glucose 6 phosphate; GLUT, glucose transporter; GS, glycogen synthase; GSK, glycogen synthase kinase; GSV, glucose transporter storage vesicle; IRS, insulin receptor substrate; IMCL, intramyocellular lipids; MAPK, mitogen-activated protein kinase; NEFA, non-esterified fatty acids; [57,63,64,[66][67][68][69]).…”