scholarly journals Berberine Reduces Lipid Accumulation by Promoting Fatty Acid Oxidation in Renal Tubular Epithelial Cells of the Diabetic Kidney

2022 ◽  
Vol 12 ◽  
Author(s):  
Qingfeng Rong ◽  
Baosheng Han ◽  
Yafeng Li ◽  
Haizhen Yin ◽  
Jing Li ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Epithelial Cells ◽  
Fatty Acid Oxidation ◽  
High Glucose ◽  
Lipid Accumulation ◽  
Diabetic Kidney Disease ◽  
Acid Oxidation ◽  
Tubular Epithelial Cells ◽  
Diabetic Kidney ◽  
Renal Tubular

Abnormal lipid metabolism in renal tubular epithelial cells contributes to renal lipid accumulation and disturbed mitochondrial bioenergetics which are important in diabetic kidney disease. Berberine, the major active constituent of Rhizoma coptidis and Cortex phellodendri, is involved in regulating glucose and lipid metabolism. The present study aimed to investigate the protective effects of berberine on lipid accumulation in tubular epithelial cells of diabetic kidney disease. We treated type 2 diabetic db/db mice with berberine (300 mg/kg) for 12 weeks. Berberine treatment improved the physical and biochemical parameters of the db/db mice compared with db/m mice. In addition, berberine decreased intracellular lipid accumulation and increased the expression of fatty acid oxidation enzymes CPT1, ACOX1 and PPAR-α in tubular epithelial cells of db/db mice. The mitochondrial morphology, mitochondrial membrane potential, cytochrome c oxidase activity, mitochondrial reactive oxygen species, and mitochondrial ATP production in db/db mice kidneys were significantly improved by berberine. Berberine intervention activated the AMPK pathway and increased the level of PGC-1α. In vitro berberine suppressed high glucose-induced lipid accumulation and reversed high glucose-induced reduction of fatty acid oxidation enzymes in HK-2 cells. Importantly, in HK-2 cells, berberine treatment blocked the change in metabolism from fatty acid oxidation to glycolysis under high glucose condition. Moreover, berberine restored high glucose-induced dysfunctional mitochondria. These data suggested that berberine alleviates diabetic renal tubulointerstitial injury through improving high glucose-induced reduction of fatty acid oxidation, alleviates lipid deposition, and protect mitochondria in tubular epithelial cells.

scholarly journals Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development

2014 ◽  
Vol 21 (1) ◽  
pp. 37-46 ◽  
Author(s):  
Hyun Mi Kang ◽  
Seon Ho Ahn ◽  
Peter Choi ◽  
Yi-An Ko ◽  
Seung Hyeok Han ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Epithelial Cells ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Tubular Epithelial Cells ◽  
Renal Tubular Epithelial Cells ◽  
Kidney Fibrosis ◽  
Renal Tubular

scholarly journals Phosphorylation of Acetyl-CoA Carboxylase by AMPK Reduces Renal Fibrosis and Is Essential for the Anti-Fibrotic Effect of Metformin

2018 ◽  
Vol 29 (9) ◽  
pp. 2326-2336 ◽  
Author(s):  
Mardiana Lee ◽  
Marina Katerelos ◽  
Kurt Gleich ◽  
Sandra Galic ◽  
Bruce E. Kemp ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Epithelial Cells ◽  
Lipid Accumulation ◽  
Acid Oxidation ◽  
Acetyl Coa Carboxylase ◽  
Tubular Epithelial Cells ◽  
Acetyl Coa ◽  
Expression Of Genes ◽  
Energy Sensing ◽  
Unilateral Ureteric Obstruction

BackgroundExpression of genes regulating fatty acid metabolism is reduced in tubular epithelial cells from kidneys with tubulointerstitial fibrosis (TIF), thus decreasing the energy produced by fatty acid oxidation (FAO). Acetyl-CoA carboxylase (ACC), a target for the energy-sensing AMP-activating protein kinase (AMPK), is the major controller of the rate of FAO within cells. Metformin has a well described antifibrotic effect, and increases phosphorylation of ACC by AMPK, thereby increasing FAO.MethodsWe evaluated phosphorylation of ACC in cell and mouse nephropathy models, as well as the effects of metformin administration in mice with and without mutations that reduce ACC phosphorylation.ResultsReduced phosphorylation of ACC on the AMPK site Ser79 occurred in both tubular epithelial cells treated with folate to mimic cellular injury and in wild-type (WT) mice after induction of the folic acid nephropathy model. When this effect was exaggerated in mice with knock-in (KI) Ser to Ala mutations of the phosphorylation sites in ACC, lipid accumulation and fibrosis increased significantly compared with WT. The effect of ACC phosphorylation on fibrosis was confirmed in the unilateral ureteric obstruction model, which showed significantly increased lipid accumulation and fibrosis in the KI mice. Metformin use was associated with significantly reduced fibrosis and lipid accumulation in WT mice. In contrast, in the KI mice, the drug was associated with worsened fibrosis.ConclusionsThese data indicate that reduced phosphorylation of ACC after renal injury contributes to the development of TIF, and that phosphorylation of ACC is required for metformin’s antifibrotic action in the kidney.

scholarly journals Sirtuin 5 Regulates Proximal Tubule Fatty Acid Oxidation to Protect against AKI

2019 ◽  
Vol 30 (12) ◽  
pp. 2384-2398 ◽  
Author(s):  
Takuto Chiba ◽  
Kevin D. Peasley ◽  
Kasey R. Cargill ◽  
Katherine V. Maringer ◽  
Sivakama S. Bharathi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Epithelial Cells ◽  
Proximal Tubule ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Tubular Epithelial Cells ◽  
Peroxisomal Fatty Acid Oxidation ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Peroxisomal Fatty Acid

BackgroundThe primary site of damage during AKI, proximal tubular epithelial cells, are highly metabolically active, relying on fatty acids to meet their energy demands. These cells are rich in mitochondria and peroxisomes, the two organelles that mediate fatty acid oxidation. Emerging evidence shows that both fatty acid pathways are regulated by reversible posttranslational modifications, particularly by lysine acylation. Sirtuin 5 (Sirt5), which localizes to both mitochondria and peroxisomes, reverses post-translational lysine acylation on several enzymes involved in fatty acid oxidation. However, the role of the Sirt5 in regulating kidney energy metabolism has yet to be determined.MethodsWe subjected male Sirt5-deficient mice (either +/− or −/−) and wild-type controls, as well as isolated proximal tubule cells, to two different AKI models (ischemia-induced or cisplatin-induced AKI). We assessed kidney function and injury with standard techniques and measured fatty acid oxidation by the catabolism of 14C-labeled palmitate to 14CO2.ResultsSirt5 was highly expressed in proximal tubular epithelial cells. At baseline, Sirt5 knockout (Sirt5−/−) mice had modestly decreased mitochondrial function but significantly increased fatty acid oxidation, which was localized to the peroxisome. Although no overt kidney phenotype was observed in Sirt5−/− mice, Sirt5−/− mice had significantly improved kidney function and less tissue damage compared with controls after either ischemia-induced or cisplatin-induced AKI. This coincided with higher peroxisomal fatty acid oxidation compared with mitochondria fatty acid oxidation in the Sirt5−/− proximal tubular epithelial cells.ConclusionsOur findings indicate that Sirt5 regulates the balance of mitochondrial versus peroxisomal fatty acid oxidation in proximal tubular epithelial cells to protect against injury in AKI. This novel mechanism might be leveraged for developing AKI therapies.

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