Nonalcoholic fatty liver disease (NAFLD) is a growing worldwide epidemic and an important risk factor for the development of insulin resistance, type 2 diabetes, nonalcoholic steatohepatitis (NASH), and hepatic cellular carcinoma (HCC). Despite the prevalence of NAFLD, lifestyle interventions involving exercise and weight loss are the only accepted treatments for this disease. Over the last decade, numerous experimental compounds have been shown to improve NAFLD in preclinical animal models, and many of these therapeutics have been shown to increase the activity of the cellular energy sensor AMP-activated protein kinase (AMPK). Because AMPK activity is reduced by inflammation, obesity, and diabetes, increasing AMPK activity has been viewed as a viable therapeutic strategy to improve NAFLD. In this review, we propose three primary mechanisms by which AMPK activation may improve NAFLD. In addition, we examine the mechanisms by which AMPK is activated. Finally, we identify 27 studies that have used AMPK activators to reduce NAFLD. Future considerations for studies examining the relationship between AMPK and NAFLD are highlighted.

Treatment of nonalcoholic fatty liver disease: role of AMPK.

AMP-activated protein kinase (AMPK) is a metabolic sensor in mammals that is activated when ATP levels in the cell decrease. AMPK is a heterotrimeric protein that comprises 3 subunits, each of which has multiple phosphorylation sites that play critical roles in the regulation of either anabolism or catabolism by directly phosphorylating proteins or modulating gene transcription in multiple pathways, such as synthesis, oxidation and lipolysis of lipid. Research focused on the phosphorylation sites that are involved in lipid metabolism will lead to a better recognition of the role of AMPK in therapeutics for several common diseases. In this review, close attention is paid to the recent research on the structure, and multisite phosphorylation of AMPK subunits, as well as AMPK regulation of lipid metabolism via phosphorylation of related molecules.

AMPK-Mediated Regulation of Lipid Metabolism by Phosphorylation.

Diabetes has become the most common metabolic disease worldwide. In particular, type 2 diabetes is the most commonly encountered type of diabetes, which is characterised by the inability of the organism to respond to normal levels of circulating insulin, also called insulin resistance. Current antidiabetic therapy is based on synthetic drugs that very often have side effects. For this reason, there is a continuous need to develop new and better pharmaceuticals as alternatives for the management and treatment of the disease. Natural hypoglycaemic compounds may be attractive alternatives to synthetic drugs or reinforcements to currently used treatments. Their huge advantage is that they can be ingested in everyday diet. Recently, more attention is being paid to the study of natural products as potential antidiabetics. This mini review of the current literature is structured into three main sections focused on: (a) plant extracts, (b) plant biomolecules, and (c) other natural molecules that have been used for their antidiabetic effects. Potential molecular mechanisms of action are also discussed.

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Plants and natural compounds with antidiabetic action.

Purple sweet potato anthocyanins attenuate hepatic lipid accumulation through activating adenosine monophosphate–activated protein kinase in human HepG2 cells and obese mice

Antifungal activity of novel synthetic peptides by accumulation of reactive oxygen species (ROS) and disruption of cell wall against Candida albicans.

Piperidine alkaloids from Piper retrofractum Vahl. protect against high-fat diet-induced obesity by regulating lipid metabolism and activating AMP-activated protein kinase.

Nordihydroguaiaretic acid protects against high-fat diet-induced fatty liver by activating AMP-activated protein kinase in obese mice

Candida species are responsible for the fourth most common nosocominal bloodstream infection. Xanthorrhizol, a sesquiterpene compound isolated from Curcuma xanthorrhiza Roxb. has been reported to have anticandidal activity. The aim of this study is to investigate the synergistic anticandidal effect of xanthorrhizol in combination with ketoconazole or amphotericin B against Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida parapsilosis, and Candida tropicalis. Mostly, xanthorrhizol in combination with ketoconazole or amphotericin B exhibited the synergistic anticandidal effects against all species of Candida tested. In combination with xanthorrhizol, the concentration of ketoconazole or amphotericin B for inhibiting the growth of the tested Candida species could be reduced by >/=50%. Time-kill curves showed that 1/2 minimum inhibitory concentration (MIC) dose of xanthorrhizol, amphotericin B, or ketoconazole alone against each of the six Candida species did not inhibit the growth of all Candida species tested. However, 1/2 MIC dose of xanthorrhizol in combination with 1/2 MIC dose of ketoconazole or 1/2 MIC dose of amphotericin B exhibited growth inhibition of all Candida species tested and reduced viable cells by several logs within 4 h. These results support the potential use of xanthorrhizol as an anticandidal agent, and it can be used complementarily with other conventional antifungal agents.

http://biofarmaka.ipb.ac.id/biofarmaka/2009/Synergistic%20Anticandidal%20Activity%20of%20Xanthorrhizol%20in%20Combination%20with%20Ketoconazole%20or%20Amphotericin%20B.pdf

Synergistic anticandidal activity of xanthorrhizol in combination with ketoconazole or amphotericin B.

Hepatic lipid accumulation is a major risk factor for dyslipidemia, nonalcoholic fatty liver disease, and insulin resistance. The present study was conducted to evaluate hypolipidemic effects of meso-dihydroguaiaretic acid (MDA), anti-oxidative and anti-inflammatory compound isolated from the Myristica fragrans HOUTT., by oil red O staining, reverse transcription-polymerase chain reaction (RT-PCR), and Western blot. MDA significantly inhibited insulin-induced hepatic lipid accumulation in a dose-dependent manner. The lipid-lowering effect of MDA was accompanied by increased expression of proteins involved in fatty acid oxidation and decreased expression of lipid synthetic proteins. In addition, MDA activated AMP-activated protein kinase (AMPK) as determined by phosphorylation of acetyl-CoA carboxylase (ACC), a downstream target of AMPK. The effects of MDA on lipogenic protein expression were suppressed by pretreatment with compound C, an AMPK inhibitor. Taken together, these findings show that MDA inhibits insulin-induced lipid accumulation in human HepG2 cells by suppressing expression of lipogenic proteins through AMPK signaling, suggesting a potent lipid-lowering agent.

Myoung Su Lee

Papers

Piperidine alkaloids from Piper retrofractum Vahl. protect against high-fat diet-induced obesity by regulating lipid metabolism and activating AMP-activated protein kinase.

Nordihydroguaiaretic acid protects against high-fat diet-induced fatty liver by activating AMP-activated protein kinase in obese mice

Synergistic anticandidal activity of xanthorrhizol in combination with ketoconazole or amphotericin B.

meso-Dihydroguaiaretic Acid Inhibits Hepatic Lipid Accumulation by Activating AMP-Activated Protein Kinase in Human HepG2 Cells