Pyruvate dehydrogenase kinase 4 mediates lipogenesis and contributes to the pathogenesis of nonalcoholic steatohepatitis

Journal Article · Mon Jan 15 04:00:00 EST 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2017.11.054· OSTI ID:23134448

Zhang, Ming; Zhao, Yujie; Li, Zhen ^[1]; Wang, Congying ^[2]

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1. Intensive Care Unit, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, 261031 (China)
2. Department of Medical Equipment, Weifang People's Hospital, Weifang, Shandong, 261000 (China)

Highlights: • The expression of PDK4 is increased in both NAFLD human and mice. • Pdk4 deficiency results in impaired glucose and lipid metabolism in the liver. • Pdk4 deficiency ameliorated hepatic steatosis in NASH mice. • Multiple hepatic signaling pathways are altered by Pdk4 deficiency. Nonalcoholic steatohepatitis (NASH) is a progressive disease and poses a high risk of severe liver damage. However, the pathogenesis of NASH is still unclear. Accumulation of lipid droplets and insulin resistance is the hallmark of NASH. Pyruvate dehydrogenase kinase isoenzyme 4 (PDK4) plays key role in glucose metabolism via regulating the activity of pyruvate dehydrogenase complex (PDC). Here, we demonstrated a novel of PDK4 in NASH by regulating hepatic steatosis and insulin signaling pathway in methionine and choline deficient (MCD) diet induced NASH model. Hepatic PDK4 levels were highly induced in human patients with NASH and MCD diet fed mice, as well as in hepatocytes treated with oleic acid. The glucose and lipid metabolism were impaired in Pdk4{sup −/−} mice. Pdk4 deficiency ameliorated the hepatic steatosis significantly in NASH mice. Pdk4{sup −/−}-MCD mice had reduced liver weights and triglyceride (TG) levels. And Pdk4 deficiency dramatically reduced the expression of genes related to fatty acid uptake, synthesis and gluconeogenesis. In addition, elevated phosphorylated AMPK (p-AMPK), p-SAPK/JNK and diminished p-ERK, p-P38, p-Akt and p-mTOR/p-4EBP1 proteins were observed. In conclusion, our data indicated that PDK4 potentially contributes to the hepatic steatosis in NASH via regulating several signaling pathway and PDK4 may be a new therapeutic strategy against NAFLD.

• OSTI ID: 23134448
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 1 Vol. 495; ISSN BBRCA9; ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
GLUCOSE
INSULIN
ISOENZYMES
LIVER
LIVER CELLS
METABOLISM
METHIONINE
MICE
OXIDOREDUCTASES
PATHOGENESIS
TRIGLYCERIDES