AMPK-Mediated Regulation of Lipid Metabolism by Phosphorylation

Wang, Qi; Liu, Shudong; Zhai, Aihua; Zhang, Bai; Tian, Guizhen

doi:10.1248/bpb.b17-00724

Cited by 194 publications

(163 citation statements)

References 82 publications

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“…The LDL receptor is regulated through sterol regulatory elementbinding protein 2 (SREBP-2), which has an important role in hepatic cholesterol homeostasis (Hua et al, 1993). SREBP-2 is down-regulated by AMP-activated protein kinase α (AMPKα) (Wang et al, 2018), and a recent study found enhancement of AMPKα expression in D-allulosefed rats (Chen et al, 2019). These findings suggest the possibility that D-allulose might down-regulate the LDL receptor by suppression of SREBP-2 through enhancement of AMPKα expression.…”

Section: Discussionmentioning

confidence: 99%

Safety and efficacy of a 48-week long-term ingestion of D-allulose in subjects with high LDL cholesterol levels

Tanaka

Kanasaki

Hayashi

et al. 2020

Fundam. Toxicol. Sci.

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-D-allulose is one of the rare sugars with almost zero calories and several health benefits. Previous studies have reported the safety of D-allulose in normal, overweight/obese, and diabetic humans. However, one study reported significant increases in T-Cho and LDL-C after 12 weeks of D-allulose intake; this report was not a randomized controlled trial and these changes were considered to be due to seasonal variations. We, therefore, conducted a randomized, double-blind, placebo-controlled trial in 90 subjects with high LDL-C levels for 48 weeks to clarify the influence of long-term D-allulose consumption on cholesterol metabolism and efficacy. Subjects were randomly divided into 3 groups: highdose D-allulose (15 g D-allulose/day), low-dose D-allulose (5 g D-allulose/day), and placebo group (0 g D-allulose/day); each subject consumed a daily test beverage for 48 weeks. Clinical examinations were performed every eight weeks, beginning from initial consumption until week 52. No significant increases in T-Cho and LDL-C between test groups were observed, and 48 weeks of D-allulose consumption did not change risk factors for atherosclerotic cardiovascular disease. Furthermore, no clinical problems were recognized for other parameters. Additionally, significant improvements in hepatic enzyme activities, fatty liver score, and glucose metabolism after long-term D-allulose consumption were observed. The results from our study revealed that 1) D-allulose consumption is considered safe for long-term intake up to a year, and 2) D-allulose may be effective for improving hepatic functions and glucose metabolism.

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Section: Discussionmentioning

confidence: 99%

Safety and efficacy of a 48-week long-term ingestion of D-allulose in subjects with high LDL cholesterol levels

Tanaka

Kanasaki

Hayashi

et al. 2020

Fundam. Toxicol. Sci.

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“…In mice, mTORC1 signaling was regulated in a tissue‐dependent manner by a ketogenic diet (Roberts et al, ). Like TOR, AMPK is a metabolic sensor that regulates the synthesis, oxidation, and lipolysis of lipids (Wang, Liu, Zhai, Zhang, & Tian, ). In the mouse study which showed that FAT10 knockout mice live longer, the authors noted that these mice had increased AMPK activity in skeletal muscle (Canaan et al, ).…”

Section: Lipid‐related Aging Mechanismsmentioning

confidence: 99%

The role of lipid metabolism in aging, lifespan regulation, and age‐related disease

2019

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An emerging body of data suggests that lipid metabolism has an important role to play in the aging process. Indeed, a plethora of dietary, pharmacological, genetic, and surgical lipid‐related interventions extend lifespan in nematodes, fruit flies, mice, and rats. For example, the impairment of genes involved in ceramide and sphingolipid synthesis extends lifespan in both worms and flies. The overexpression of fatty acid amide hydrolase or lysosomal lipase prolongs life in Caenorhabditis elegans, while the overexpression of diacylglycerol lipase enhances longevity in both C. elegans and Drosophila melanogaster. The surgical removal of adipose tissue extends lifespan in rats, and increased expression of apolipoprotein D enhances survival in both flies and mice. Mouse lifespan can be additionally extended by the genetic deletion of diacylglycerol acyltransferase 1, treatment with the steroid 17‐α‐estradiol, or a ketogenic diet. Moreover, deletion of the phospholipase A2 receptor improves various healthspan parameters in a progeria mouse model. Genome‐wide association studies have found several lipid‐related variants to be associated with human aging. For example, the epsilon 2 and epsilon 4 alleles of apolipoprotein E are associated with extreme longevity and late‐onset neurodegenerative disease, respectively. In humans, blood triglyceride levels tend to increase, while blood lysophosphatidylcholine levels tend to decrease with age. Specific sphingolipid and phospholipid blood profiles have also been shown to change with age and are associated with exceptional human longevity. These data suggest that lipid‐related interventions may improve human healthspan and that blood lipids likely represent a rich source of human aging biomarkers.

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“…Another signal potentially involved in lipotoxicity-mediated tubular damage is the AMPK-PGC-1α pathway. As this pathway activity decreases, an increase in the intra-cytoplasmic triglyceride synthesis and accumulation is observed [151]. PGC-1α, a key regulator of mitochondrial biogenesis and energy metabolism, is proposed as one of the main therapeutic targets in acute kidney damage, CKD, and DN [152][153][154][155][156][157].…”

Section: Lipotoxicity In Renal Cellsmentioning

confidence: 99%

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

Opazo-Ríos

Mas

Marín-Royo

et al. 2020

IJMS

192

147

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Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.

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AMPK-Mediated Regulation of Lipid Metabolism by Phosphorylation

Cited by 194 publications

References 82 publications

Safety and efficacy of a 48-week long-term ingestion of D-allulose in subjects with high LDL cholesterol levels

Safety and efficacy of a 48-week long-term ingestion of D-allulose in subjects with high LDL cholesterol levels

The role of lipid metabolism in aging, lifespan regulation, and age‐related disease

Lipotoxicity and Diabetic Nephropathy: Novel Mechanistic Insights and Therapeutic Opportunities

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