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Barshop Institute for Longevity and Aging Studies

Xianlin Han, Ph.D.

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Xianlin Han, Ph.D.

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Professor
Department of Medicine
Sam and Ann Barshop Institute for Longevity and Aging Studies
UT Health San Antonio
Phone: 210-562-4104

RESEARCH

Our research is focused on identification of the molecular and biochemical mechanisms underlying alterations in lipid metabolism, signaling, and homeostasis that occur under patho(physio)logical conditions such as aging, Alzheimer’s disease (AD), diabetes, and cancer by lipidomics. Lipid metabolism spans a highly elaborate system comprised of numerous classes and subclasses, and hundreds of thousands of lipid species that make up the cellular lipidomes. A large number of pathways and networks which are highly dynamic and interwoven are involved in lipid metabolism. Identifying the mechanisms underpinning alterations in lipid metabolism, signaling, and homeostasis that occur under patho(physio)logical conditions could unravel disease pathogenesis, uncover drug targets for treatment, and identify biomarkers for early diagnosis and prognosis of the diseases. Lipidomics, which facilitates large-scale analysis of cellular lipidomes based on the principles and techniques of analytical chemistry, could allow one to comprehensively and effectively determine alterations in lipid metabolism, signaling, and homeostasis under the conditions.

Our laboratory is the world-leading research group on lipidomics. We have developed an enabling technology with in-house software programs termed “multi-dimensional mass spectrometry-based shotgun lipidomics (MDMS-SL)”, initiated in the early 1990s and still under constant evolution. The MDMS-SL technology provides modular, robust, and label-free quantification of lipids. At its current stage, the technology enables us to identify and quantify nearly 50 lipid classes, over 95% of lipid mass content, and thousands of individual lipid molecular species from limited amounts of biological samples in an accurate (>90% reproducibility) and relatively high throughput fashion. By using lipidomics, we have developed a few research projects (supported with NIH funds and other sources) including AD and diabetes-associated dementia (outlined below), as well as multiple minor translational research projects such as anesthetics-induced neurotoxicity and cancer biomarkers. Finally, using our enabling lipidomics technology, we have established numerous (inter)national collaborations on a variety of research areas.

Altered lipid metabolism and AD pathogenesis 

AD, a progressive neurodegenerative disorder, is the most common cause of dementia in the aging population. AD is characterized clinically by progressive cognitive impairment and neuropathologically by the appearance of soluble amyloid-beta (Ab), neuritic plaques, neurofibrillary tangles, and glial activation. Currently, there is no cure or preventive therapy for AD. The failures of hundreds of trials of disease-modifying therapeutics, including many targeting Aβ highlight our incomplete knowledge of both cause of AD and mechanisms of cognitive failure. Because of its high prevalence and the continuing increase of the aged population, AD is a major health problem with serious negative impacts on affected individuals and their families, as well as on local and global economies.

By using lipidomics, we previously revealed marked losses of sulfatide and plasmalogen, and drastic increases in ceramide at the earliest clinically recognizable stages of AD subjects and in animal models examined. Mechanistic studies uncovered the altered metabolism of sulfatide through apolipoprotein E (apoE) transport in an isoform-dependent manner. The reduction of sulfatide content is parallel to Ab deposition/fibrillation. Depletion of sulfatide results in Ab oligomerization, tau hyperphosphorylation, fibrous astrogliosis, and cognitive decline. Our current research on this project is focused on elucidating the causal connection of sulfatide deficiency to AD hallmarks by applying lipidomics, histology, biochemistry, animal behavioral studies, and other molecular and cellular approaches on murine and human cells, fluids, and tissues. For example, we are currently exploiting a novel inducible oligodendrocyte-specific conditional sulfatide-deficiency mouse line and other multiple knockin or transgenic AD animal models. We believe these innovative studies will allow us to understand the AD pathogenesis and identify potential drug targets for treatment/prevention of AD.

Lipidomics for studying diabetes-induced dementia and complications 

Diabetes, another aging-associated disease, is one of the major epidemiological risk factors for dementia, including AD. Diabetes leads to many complications including diabetic neuropathy. Roughly 10% of the U.S. population has diabetes and there will be an estimated 366 million people with diabetes worldwide by 2030. Despite recent great success in treatment of diabetes, effective prevention and treatment of diabetic complications and diabetes-induced dementia are still lagged. As diabetes and its complications become an urgent public health issue and a global economic burden, identification of the causal mechanisms responsible for its complications becomes a priority.

Recently, by using lipidomics, we determined alterations in the lipidomes of multiple organ/tissue samples from a number of animal models of both type 1 and type 2 diabetes in a temporal manner. We revealed that marked losses of myelin lipids progressed from peripheral nerves to the central nervous system early in type 2 diabetic models, but not in the type 1 model. These findings suggest that the disruption of myelin lipid homeostasis and nerve function in type 2 diabetes is not caused by hyperglycemia, as it was previously assumed (but not proven). We further demonstrated substantial accumulation of non-esterified fatty acids and triglycerides in sciatic nerves, leading to “fatty nerves”. Both myelin loss and “fatty nerves” precede the loss of myelin proteins and axonal damage that result in reduced nerve conductivity. Mechanistic studies unraveled nerve mitochondrial impairment including reduced fatty acid oxidation and respiratory activities. Our current research on this project is focused on identifying the causal factors for myelin loss, “fatty nerves”, mitochondrial dysfunction, nerve damage, and loss of conductivity. We are using a variety of animal models including conditional knockout mouse lines and exploiting lipidomics, histology, biochemistry, electrophysiology, and other molecular and cellular approaches for the project. We believe these innovative studies will allow us to identify the molecular and biochemical mechanisms responsible for diabetic complications and diabetes-induced dementia, that will hopefully lead to better treatments.

SELECTED PUBLICATIONS

  1. Wang, C., Liu, F., Frisch-Daiello, J.L., Martin, S., Patterson, T.A., Gu, Q., Liu, S., Paule, M.G., Hanig, J.P., Slikker, Jr., W., Crawford, P.A., Wang, C., and Han, X. (2018) Lipidomics reveals a systemic energy deficient state that precedes neurotoxicity in neonatal monkeys after sevoflurane exposure. Anal. Chim. Acta doi: 10.1016/j.aca.2017.11.052.
  2. Wang, M., Palavicini, J.P., Cseresznye, A., and Han, X. (2017) Strategy for quantitative analysis of isomeric bis(monoacylglycero)phosphate and phosphatidylglycerol species by shotgun lipidomics after one-step methylation. Anal. Chem. 89, 8490-8495.
  3. Palavicini, J.P., Wang, C., Chen, L., Hosang, K., Wang, J., Tomiyama, T., Mori, H., and Han, X. (2017) Oligomeric amyloid-beta induces MAPK-mediated activation of brain cytosolic and calcium-independent phospholipase A2 in a spatial-specific manner. Acta Neuropathol. Commun. 5, 56.
  4. Wang, M., Wang, C., and Han, X. (2017) Selection of internal standards for accurate quantification of complex lipid species in biological extracts by electrospray ionization mass spectrometry – What, how and why? Mass Spectrom. Rev. 36, 693-714.
  5. Hu, C., Wang, M., and Han, X. (2017) Shotgun lipidomics in substantiating lipid peroxidation in redox biology: Methods and applications. Redox Biol. 12, 946-955.

 
 
   
 

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The Sam and Ann Barshop Institute for Longevity and Aging Studies

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P: 210-562-6140 F: 210-562-6150

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