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Open AccessArticle

Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism

Division of Endocrinology, Metabolism, & Diabetes, Denver Anschutz Medical Campus, University of Colorado, Aurora, CO 80045, USA
Department of Medicine, University of Colorado, Denver Anschutz Medical Campus, Aurora, CO 80045, USA
Department of Physiology, School of Medicine, Tulane University, New Orleans, LA 70112, USA
Department of Biochemistry and Molecular & Cellular Biology, Georgetown University Medical Center, Washington, DC 20057, USA
Author to whom correspondence should be addressed.
Metabolites 2020, 10(10), 385;
Received: 31 July 2020 / Revised: 31 August 2020 / Accepted: 21 September 2020 / Published: 28 September 2020
(This article belongs to the Special Issue Lipid and Lipoprotein Metabolism)
The autonomic regulation of hepatic metabolism offers a novel target for the treatment of non-alcoholic fatty liver disease (NAFLD). However, the molecular characteristics of neurons that regulate the brain-liver axis remain unclear. Since mice lacking neuronal lipoprotein lipase (LPL) develop perturbations in neuronal lipid-sensing and systemic energy balance, we reasoned that LPL might be a component of pre-autonomic neurons involved in the regulation of hepatic metabolism. Here, we show that, despite obesity, mice with reduced neuronal LPL (NEXCreLPLflox (LPL KD)) show improved glucose tolerance and reduced hepatic lipid accumulation with aging compared to wilt type (WT) controls (LPLflox). To determine the effect of LPL deficiency on neuronal physiology, liver-related neurons were identified in the paraventricular nucleus (PVN) of the hypothalamus using the transsynaptic retrograde tracer PRV-152. Patch-clamp studies revealed reduced inhibitory post-synaptic currents in liver-related neurons of LPL KD mice. Fluorescence lifetime imaging microscopy (FLIM) was used to visualize metabolic changes in LPL-depleted neurons. Quantification of free vs. bound nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) revealed increased glucose utilization and TCA cycle flux in LPL-depleted neurons compared to controls. Global metabolomics from hypothalamic cell lines either deficient in or over-expressing LPL recapitulated these findings. Our data suggest that LPL is a novel feature of liver-related preautonomic neurons in the PVN. Moreover, LPL loss is sufficient to cause changes in neuronal substrate utilization and function, which may precede changes in hepatic metabolism. View Full-Text
Keywords: lipoprotein lipase; neuronal metabolism; fatty liver; brain-liver axis; FLIM lipoprotein lipase; neuronal metabolism; fatty liver; brain-liver axis; FLIM
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Bruce, K.D.; Dobrinskikh, E.; Wang, H.; Rudenko, I.; Gao, H.; Libby, A.E.; Gorkhali, S.; Yu, T.; Zsombok, A.; Eckel, R.H. Neuronal Lipoprotein Lipase Deficiency Alters Neuronal Function and Hepatic Metabolism. Metabolites 2020, 10, 385.

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