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    • AMPK modulates changes in lipid metabolism via the regulatio

    2023-02-06

    AMPK modulates changes in lipid metabolism via the regulation of fatty mexiletine hcl oxidation and cholesterol synthesis in the liver. The key enzymes involved include ACC and HMGCR [27,28]. Both participate in the rate-limiting steps of fatty acids and cholesterol synthesis and are inactivated on phosphorylation by AMPK. Catabolism is induced by fatty acid beta-oxidation, leading to the production of acetyl-CoA, which then joins the citric acid cycle to generate ATP. On the other hand, fatty acid synthesis is a multistep, energy-consuming, anabolic process that generates fatty acids from acetyl-CoA and malonyl-CoA. Likewise, cholesterol is synthesized from acetyl-CoA to produce 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA), which is then converted into mevalonate through an anabolic process that consumes ATP. Hence, in response to energy depletion, the inhibition of ACC by AMPK results in a fall in malonyl-CoA levels and subsequently interrupts fatty acid synthesis, facilitating the acceleration of fatty acid oxidation. Through the activation of malonyl-CoA decarboxylase, AMPK brings about a decrease in malonyl-CoA levels and an increase in fatty acid oxidation. Likewise, HMGCR is inactivated on phosphorylation, which leads to a reduction in cholesterol synthesis. In addition, the expression of such genes as fatty acid synthase, pyruvate kinase, ACC, and sterol regulatory element–binding protein-1 (SREBP-1) is lipogenesis associated and suppressed by AMPK in states of energy deficit [29]. Emerging evidence indicates that renal lipid dysregulation is a major causative factor in the development of CKD, along with DN [30]. Recently, it has been characterized by tubular rather than glomerular lipid accumulation, attributable to decreased lipid uptake, increased renal lipid synthesis, and defective fatty acid utilization in the renal physiology [19]. Systemic and intrarenal alterations in lipid metabolism are reflected by increased triglycerides and low-density lipoprotein levels, decreased high-density lipoprotein levels, increased expression of SREBP-1 and fatty acid synthase, and decreased expression of carnitine palmitoyltransferase I, which is involved in the rate-limiting step of fatty acid oxidation [31]. AMPK inhibits lipogenesis and enhances fatty acid oxidation through targets such as SREBP, ACC, fatty acid synthase, and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR) in various tissues. This raises the potential for AMPK activation as a therapeutic target in optimizing lipid metabolism in DN [32]. AMPK perceives shifts in the surrounding energy reservoir and adapts to the nutrient supply status by promoting a cellular response. It participates in protein synthesis by regulating protein translation. Its main targets are cytoplasmic substrates, such as eukaryotic elongation factor 2 and mTOR, which modulate the stimulation of cellular processes that aid cell growth in states of nutritional surplus [33]. On AMPK-dependent phosphorylation of these substrates, repression of protein synthesis ensues. It could be useful to coordinate these processes in DN as they correlate with diminished AMPK activity, resulting in increases in protein synthesis that can cause diabetes-induced renal hypertrophy in hyperglycemic conditions. Thus, specifically stimulating cytoplasmic AMPK could provide a more focused approach in alleviating diabetes-induced renal damage [34].
    Managing DN by targeting the AMPK pathway In parallel with a vast and rapidly growing body of knowledge on the favorable effects of AMPK, of which only a fragment has been discussed, investigators have devised several pharmaceutical agents in the search for naturally occurring compounds that could activate AMPK with minimal toxicity. We will introduce some conventional AMPK activators, along with our data on new therapeutic agents used to experimentally treat diabetic mouse models addressing DN (Figs. 2, 3).
    Conventional AMPK activators 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) is an adenosine analogue that is frequently demonstrated in animal models as it recapitulates AMP in the course of being metabolized to phosphorylated AICA riboside or AICA ribotide [AICAR 5-monophosphate (ZMP)] (Fig. 2) [35]. ZMP binding to the γ subunit of AMPK directly activates AMPK via 3 mechanisms: accelerating phosphorylation, inhibiting dephosphorylation, and allosterical activation [35,36]. AICAR upregulates genes associated with oxidative metabolism, angiogenesis, and glucose sparing, thereby improving glucose homeostasis in obese, insulin-resistant rats [37]. Moreover, a recent report on chronic AICAR treatment shows its efficacy in preventing unfavorable functional and morphologic changes in mice raised on high-fat diets, with regard to renal cholesterol and phospholipid accumulation and lysosomal system dysfunction; this demonstrates that AICAR in a viable form may be a promising agent in alleviating the deleterious outcomes of DN [38].