Submitted on November 27, 2007
Accepted on May 21, 2008
The lowering of hepatic fatty acid uptake improves liver function and insulin sensitivity without affecting hepatic fat content in humans
Sara Rigazio1, Hanna-Riikka Lehto1, Helena Tuunanen1, Kjell Nagren1, Mikko Kankaanpaa1, Claudia Simi2, Ronald Borra1, Alexandru G Naum1, Riitta Parkkola3, Juhani Knuuti1, Pirjo Nuutila1, and Patricia Iozzo4*
1 Turku PET Centre, University of Turku, Turku, Finland
2 Institute of Clinical Physiology, National Research Council, Pisa, Italy
3 Dept. of Radiology, University of Turku, Turku, Finland
4 Turku PET Centre, University of Turku, Turku, Finland; Institute of Clinical Physiology, National Research Council, Pisa, Italy
* To whom correspondence should be addressed. E-mail: patricia.iozzo{at}ifc.cnr.it.
Background/Aims Lipolysis may regulate liver free fatty acid (FFA) uptake and triglyceride accumulation; both are potential causes of insulin resistance and liver damage. We evaluated if a) systemic FFA release is the major determinant of liver FFA uptake in fasting humans in vivo, and b) the beneficial metabolic effects of FFA lowering can be explained by a reduction in liver triglyceride content.
Methods Sixteen healthy subjects were subdivided in two groups of similar characteristics to undergo Positron Emission Tomography with 11C-acetate and 11C-palmitate to quantify liver FFA metabolism (n=8), or Magnetic Resonance Spectroscopy (MRS) to measure hepatic fat content (n=8), before and after the acute lowering of circulating FFA by using the antilipolytic agent acipimox. MRS was again repeated after a one-week treatment period.
Results Acipimox suppressed FFA levels, while stimulating hepatic fractional extraction of FFA (p<0.05); as a result, fasting liver FFA uptake was decreased by 79% (p=0.0002) in tight association with lipolysis (r=0.996, p<0.0001). The one-week treatment induced a significant improvement in systemic (+30%) and liver (+70%) insulin sensitivity (p<0.05), and decreased circulating triglycerides (-20%, p=0.06) and liver enzymes (ALT -20%, p=0.03). No change in liver fat content was observed after either acute or sustained FFA suppression.
Conclusion Acute and sustained inhibitions of lipolysis and liver FFA uptake fail to deplete liver fat in healthy human subjects. Liver FFA uptake was decreased in proportion to FFA delivery. As consequence, liver and systemic insulin sensitivity were improved, together with liver function, independent of changes in hepatic triglyceride accumulation.
