Abstract
Excessive fatty acid release from the white adipose tissue (WAT) contributes to the development of alcoholic liver disease (ALD). Lipin1 (LPIN1), as a co-regulator of DNA-bound transcription factors and a phosphatidic acid (PA) phosphatase (PAP) enzyme that dephosphorylates PA to form diacylglycerol (DAG), is dramatically reduced by alcohol in the WAT. This study aimed at determining the role of adipose LPIN1 in alcohol-induced lipodystrophy and the development of ALD. Transgenic mice overexpressing LPIN1 in adipose tissue (LPIN1-Tg) and wild type (WT) mice were fed a Lieber-DeCarli alcohol or isocaloric maltose dextrin control liquid diet for 8 weeks. Alcohol feeding to WT mice resulted in significant liver damage, which was significantly alleviated in the LPIN1-Tg mice. Alcohol feeding significantly reduced epididymal WAT (EWAT) mass, inhibited lipogenesis, and increased lipolysis in WT mice, which were attenuated in the LPIN1-Tg mice. LPIN1 overexpression also partially reversed alcohol-reduced plasma leptin levels. In WT mice, alcohol feeding induced hepatic lipid accumulation and down-regulation of beta-oxidation genes, which were dramatically alleviated in the LPIN1-Tg mice. LPIN1 overexpression also significantly attenuated alcohol-induced hepatic ER stress. These results suggest that overexpression of LPIN1 in adipose tissue restores WAT lipid storage function and secretive function to alleviate alcohol-induced liver injury.
Highlights
Excessive alcohol consumption has been shown to disrupt lipid homeostasis in the liver and is associated with the development of liver diseases, including steatosis, steatohepatitis, fibrosis, and cirrhosis[1,2,3]
epididymal WAT (EWAT) masses of wild type (WT) mice were significantly reduced by chronic alcohol feeding, adipose-specific
Ex vivo study showed that adipose-specific LPIN1 overexpression significantly inhibited acetaldehyde-induced release of FFAs from EWAT (Fig. 1D)
Summary
Excessive alcohol consumption has been shown to disrupt lipid homeostasis in the liver and is associated with the development of liver diseases, including steatosis, steatohepatitis, fibrosis, and cirrhosis[1,2,3]. Excessive alcohol consumption causes lipid dyshomeostasis at the adipose-liver axis, reducing lipid storage in white adipose tissue (WAT) and decreasing adipose mass, namely lipodystrophy[4,5,6]. As a major energy storage organ, WAT plays several key roles in mammalian physiology including storage excess energy in the form of triglycerides under positive energy balance conditions and releasing energy in the form of fatty acids under negative energy balance conditions. Leptin is a hormone secreted by adipocytes that plays a pivotal role in the regulation of glucose and lipid metabolism[11]. The present study was designed to determine the role of LPIN1 in the pathogenesis of alcohol-induced lipodystrophy and the development of ALD
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