The Impact of CLF and CASL on one Canadian Scientist, W. Wayne Lautt.
The Canadian Liver Foundation initiated a 5-year research Scholarship program in 1974. W. Wayne Lautt was the 1st Canadian Liver Foundation research Scholar, which funded his appointment as an assistant professor in the Department of Physiology at the University of Saskatchewan from1974-1979. That award proved to be highly influential in the development of his entire scientific career.
Lautt became an active member in CLF, serving on grant committees and the governing body of the society. In 1987, a group of Canadian liver researchers who had been involved with the formation and evolution of CLF, met at a Chicago Liver meeting to discuss the feasibility of expanding the role of CLF to a foundation that focused on education. Some of the main attendees included Gaby Plaa, Carl Goresky, Woody Fischer, Laury Blendis, Jim Phillips, Gerry Minuk ,and Wayne Lautt. Other attending members were present but remain unidentified.
Soon thereafter the Canadian Association for Study of Liver (CASL) was founded. The focus was intentionally not restricted to research on disease, so the title encompassed all research topics, including both basic and clinical science. Lautt was elected Founding President. Gerry Minuk was Founding Vice President and Chaired the first foundation Symposium, as President, in 1988.
The Impact of the CLF Research Scholarship Award
The awarding of the1974 Research Scholarship was pivotal in in the commencement of Lautt’s entire scientific career.
Lautt’s science has focused on the integrative dynamic functions of the liver since 1968. As a first year graduate student in the Department of Pharmacology and Therapeutics at the university of Manitoba, he, Ron Stark (a postdoctoral fellow), and Clive Greenway (Lautt’s supervisor) assembled an in vivo plethysmograph enclosing the liver with intact nerves and blood flow in a stable, anesthetized, living animal, thus allowing a wide range of novel explorations of hepatic capacitance and fluid exchange regulation and roles. In vivo drug and hormone dose-response and nerve frequency-response curves quantitated factors controlling and affecting the large venous reservoir of the liver
The next pivotal tool developed with Lautt and Stark in the Greenway lab, was the hepatic venous long circuit, a vascular preparation that diverted the hepatic outflow into a cannula in the vena cava. Vena Caval blood flow below the liver was drained via femoral venous cannulas. The blood was drained into a reservoir where it was warmed and pumped back to the jugular veins. This procedure was used with the plethysmograph, and later with measurements of the hepatic arterial and portal blood flows. The animal remained stable for at least 8 hours, thus allowing for primary and secondary hypothesis testing and ‘look-see’ pilots. Several novel discoveries were facilitated because of this unique tool.
Having completed his doctoral and post-doctoral work, and having established his own lab as a CLF scholar, Lautt was now heavily invested in liver research. Well into the period of the CLF scholarship, in 1977, the unique mechanism of regulation of the hepatic artery was defined as the hepatic arterial buffer response (HABR) whereby portal blood flow regulated hepatic arterial flow by the rate of washout of adenosine from the Space of Mall, a mechanism not used in any other vascular bed.
The overriding vascular theme pursued by Lautt extended to quantifying vascular compliance of portocaval venous shunts and hepatic vascular compliance in portal inflow and hepatic outflow blood vessels and differentiating between active and passive vascular actions of drugs and therapeutic interventions. Regulation of intestinal blood flow was compared with that of the arterial flow to the liver, using the same tools.
The trigger for liver regeneration after partial hepatectomy was discovered in 1997. Liver regeneration was shown to be regulated by shear-stress-induced nitric oxide that is activated immediately upon partial hepatectomy, triggering the regeneration cascade. Activation of the trigger was quantified using hepatocyte tissue culture exposed to blood following the surgery.
Hepatic nerves were a theme in Lautt’s PhD thesis and continue to today. In 1983, Lautt published the first review of the afferent and efferent hepatic nerves, going back to the earliest explorations of people like Ernest Starling and Claude Bernard and the extensive knowledge contributed by a strong Japanese cohort of Shimazu and Nijima. The early studies had focused on the roles and regulation of the sympathetic nerve actions on vasculature and glucose metabolism. A redundant control system was demonstrated whereby either hepatic sympathetic nerves or adrenal secretion of catecholamines resulted in a hyperglycemic response to hemorrhage.
Sensory nerve action was also explored. In 2004 the mechanism of the hepatorenal syndrome was shown to be regulated by the same adenosine-dependant mechanism as regulated the hepatic artery, whereby reduced portal flow washed out less adenosine from the space of Mall. The elevated adenosine caused both arterial dilation (HABR) and activated sensory nerves in the liver to reflexly shut down urine formation in the kidneys.
The hepatic parasympathetic nerves were found to play a major role in the most common metabolic-related dysfunctions. Stimulation of hepatic parasympathetic nerves completely shut down baseline fasting levels of hepatic glucose output (1978), initiating the published hypothesis that hepatic parasympathetic neuropathy could account for type 2 diabetic metabolic dysfunction (1980).
This line of research led to what Lautt has claimed to be the missing link in understanding type 2 diabetes and obesity with the discovery of a hepatic hormone, hepatalin, that accounts for 50% (rat)-67% (human) of what has been attributed to the direct action of insulin administered after feeding. Pulses of insulin stimulate hepatic secretion of hepatalin, but only in the postprandial state and only if two feeding signals in the liver are activated (parasympathetic nerves and elevated glutathione). Absence of this meal-induced insulin sensitization (AMIS) results in postprandial hyperglycemia, compensatory hyperinsulinemia and a shift in partitioning of nutrient energy away from glycogen in muscle to fat in liver and adipose tissue. Hepatalin actions and role in health and disease, including fatty liver has been recently reviewed (Can. J. Physiol. Pharmacol. 101:117-135 (2023). A diagnostic, a preventative and a therapeutic were designed for studies of hepatalin-dependant insulin resistance (HDIR) as research tools and have now entered clinical trials. A Manitoba based company, SciMar Ltd, was founded (2009) to bring to market the diagnostic, the daily preventative and a pre-meal therapeutic for the very common symptoms associated with reduced hepatalin action (the AMIS syndrome aka syndrome X etc.), by preserving and restoring hepatalin secretion from the liver. The first clinical trial has been completed.
The early-stage career support as a CLF research Scholar encouraged Lautt to focus on the liver from both basic acute and chronic homeodynamic perspectives. Lautt passed on this focus through decades of teaching at many levels. He introduced a fourth-year course on hepatic physiology at the University of Saskatchewan, and a graduate level course on the pharmacology and therapeutics of the liver at the University of Manitoba. He was recruited to Head the Hepato-Renal Research Unit in the Department of Pharmacology and Therapeutics at the University of Manitoba in 1984 and became Head of the Department in 1989. Lectures to Undergraduates, Medical, Pharmacy, and Graduate students has afforded an opportunity to weave the liver and its broad impact on the body, into their knowledge base.
In 1980 Lautt, with the financial support of CLF, hosted an international meeting, that resulted in a book, Hepatic Circulation in Health and Disease (Raven Press 1981). In 2010 he published a book in ‘Colloquium series in Integrated Systems Physiology: from molecule to function’, entitled Hepatic Circulation Physiology and Pathophysiology (Morgan and Claypool Life Sciences), which is a 174-page review of all aspects of the hepatic circulation. This publication is a classic educational reference text.
Lautt has received awards for contribution to science from the Canadian Physiological Society, the Canadian Pharmacological Society, the Ernesto Roma award from Portugal for contributions to diabetes research. In 2004, in the first year of the award, he received a Micheal Smith award from the Canadian Institutes for Health Research “for outstanding contribution to health research”. He continues to publish original research and reviews related to the liver, the most recent (2025) relating to prevention and treatment of diet-induced gestational diabetes based on the hepatalin paradigm.
Submitted by Dr. W. Wayne Lautt, Professor Emeritus, University of Manitoba
April 29, 2025
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