Stearoyl-CoA Desaturase-1 Protects Cells against Lipotoxicity-Mediated Apoptosis in Proximal Tubular Cells.
Saturated fatty acid (SFA)-related lipotoxicity is a pathogenesis of diabetes-related renal proximal tubular epithelial cell (PTEC) damage, closely associated with a progressive decline in renal function. This study was designed to identify a free fatty acid (FFA) metabolism-related enzyme that can protect PTECs from SFA-related lipotoxicity. Among several enzymes involved in FFA metabolism, we identified stearoyl-CoA desaturase-1 (SCD1), whose expression level significantly decreased in the kidneys of high-fat diet (HFD)-induced diabetic mice, compared with non-diabetic mice. SCD1 is an enzyme that desaturates SFAs, converting them to monounsaturated fatty acids (MUFAs), leading to the formation of neutral lipid droplets. In culture, retrovirus-mediated overexpression ofSCD1or MUFA treatment significantly ameliorated SFA-induced apoptosis in PTECs by enhancing intracellular lipid droplet formation. In contrast, siRNA againstSCD1exacerbated the apoptosis. Both overexpression ofSCD1and MUFA treatment reduced SFA-induced apoptosis via reducing endoplasmic reticulum stress in cultured PTECs. Thus, HFD-induced decrease in renal SCD1 expression may play a pathogenic role in lipotoxicity-induced renal injury, and enhancing SCD1-mediated desaturation of SFA and subsequent formation of neutral lipid droplets may become a promising therapeutic target to reduce SFA-induced lipotoxicity. The present study provides a novel insight into lipotoxicity in the pathogenesis of diabetic nephropathy.
Department of Medicine, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan. tama@belle.shiga-med.ac.jp.
Tamaki
T
Iwai
Department of Medicine, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan. skume@belle.shiga-med.ac.jp.
Shinji
S
Kume
Department of Medicine, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan. msm@belle.shiga-med.ac.jp.
Masami
M
Chin-Kanasaki
Department of Medicine, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan. skuwaga@belle.shiga-med.ac.jp.
Shogo
S
Kuwagata
Department of Medicine, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan. haraki@belle.shiga-med.ac.jp.
Hisazumi
H
Araki
Department of Medicine, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan. takedan@belle.shiga-med.ac.jp.
Naoko
N
Takeda
Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216-8511, Japan. takeshi-sugaya@marianna-u.ac.jp.
Takeshi
T
Sugaya
Department of Medicine, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan. takuzu@belle.shiga-med.ac.jp.
Takashi
T
Uzu
Department of Medicine, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan. maegawa@belle.shiga-med.ac.jp.
Hiroshi
H
Maegawa
Department of Medicine, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan. araki@belle.shiga-med.ac.jp.
Shin-Ichi
SI
Araki
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D005215:Fasting; D005227:Fatty Acids / Q000378:metabolism* / Q000633:toxicity; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism*; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000201:enzymology* / Q000473:pathology; D066292:Lipid Droplets / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D000070780:Perilipin-2 / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D001786:Blood Glucose; D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D000070780:Perilipin-2; C000602983:Plin2 protein, mouse; D034741:RNA, Small Interfering; C490333:Scd1 protein, mouse; D013230:Stearoyl-CoA Desaturase
desaturation; free fatty acid; lipid droplet; lipotoxicity; proximal tubular epithelial cells