Fatty acid regulation of hepatic lipid metabolism.

Department of Nutrition and Exercise Sciences, The Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331, USA.
Current opinion in clinical nutrition and metabolic care 03/2011; 14(2):115-20. DOI: 10.1097/MCO.0b013e328342991c
Source: PubMed

ABSTRACT To discuss transcriptional mechanisms regulating hepatic lipid metabolism.
Humans who are obese or have diabetes (NIDDM) or metabolic syndrome (MetS) have low blood and tissue levels of C20-22 polyunsaturated fatty acids (PUFAs). Although the impact of low C20-22 PUFAs on disease progression in humans is not fully understood, studies with mice have provided clues suggesting that impaired PUFA metabolism may contribute to the severity of risk factors associated with NIDDM and MetS. High fat diets promote hyperglycemia, insulin resistance and fatty liver in C57BL/6J mice, an effect that correlates with suppressed expression of enzymes involved in PUFA synthesis and decreased hepatic C20-22 PUFA content. A/J mice, in contrast, are resistant to diet-induced obesity and diabetes; these mice have elevated expression of hepatic enzymes involved in PUFA synthesis and C20-22 PUFA content. Moreover, loss-of-function and gain-of-function studies have identified fatty acid elongase (Elovl5), a key enzyme involved in PUFA synthesis, as a regulator of hepatic lipid and carbohydrate metabolism. Elovl5 activity regulates hepatic C20-22 PUFA content, signaling pathways (Akt and PP2A) and transcription factors (SREBP-1, PPARα, FoxO1 and PGC1α) that control fatty acid synthesis and gluconeogenesis.
These studies may help define novel strategies to control fatty liver and hyperglycemia associated with NIDDM and MetS.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Alpha linolenic acid (ALA, 18:3) in maternal diets has been shown to attenuate obesity associated insulin resistance (IR) in adult offspring in mice. The objective in the present study was to detect the early effects of maternal dietary saturated fatty acids (SFA) and their partial substitution with ω-3 ALA, docosa hexenoic acid (DHA,22:6) and eicosapentenoic acid 20:5 (EPA,20:5) on the HOMA index, liver lipids and fatty acid desaturases in the offspring at weaning. Methods 3 month old C57Bl6/J female mice were fed diets containing normal amount of calories but rich in SFA alone or partially replaced with ALA, DHA or EPA before mating, during pregnancy and lactation. Results Pregnant mice fed SFA produced offspring with the highest HOMA index, liver lipids and desaturase activities. ALA prevented SFA induced lipid increase but DHA and EPA only reduced it by 42% and 31% respectively. ALA, DHA and EPA decreased HOMA index by 84%, 75% and 83% respectively. ALA, DHA and EPA decreased Δ6 and SCD1 desaturase activities about 30%. Conclusions SFA feeding to mothers predisposes their offspring to develop IR and liver lipid accumulation already at weaning. ω3 fatty acids reduce IR, ALA halts lipid accumulation whereas DHA and EPA only blunt it.ALA and DHA restore the increased SCD1 to normal. These studies suggest that ω-3 fatty acids have different potencies to preclude lipid accumulation in the offspring partially by affecting pathways associated to SCD1 modulation.
    Lipids in Health and Disease 02/2015; 14(14). DOI:10.1186/s12944-015-0012-7 · 2.31 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: AMP kinase is a heterotrimeric serine/threonine protein kinase that regulates a number of metabolic processes, including lipid biosynthesis and metabolism. AMP kinase activity is regulated by phosphorylation, and the kinases involved have been uncovered. The particular phosphatases counteracting these kinases remain elusive. Here we discovered that the protein phosphatase 2A heterotrimer, PP2A,(Ppp2r2d,), regulates the phosphorylation state of AMP kinase by dephosphorylating Thr172, a residue that activates kinase activity when phosphorylated. Co-immunoprecipitation and co-localization studies indicated that PP2AP(pp2r2d) directly interacted with AMP kinase. PP2A(Ppp2r2d) dephosphorylated Thr172 in rat aortic and human vascular smooth muscle cells. This was a correlation between decreased phosphorylation and decreased acetyl-CoA carboxylase Acc1, and SREBP1c-dependent gene expression. PP2A(Ppp2r2d) protein expression was up regulated in the aortas of mice fed a high fat diet, and the increased expression correlated with increased blood lipid levels. Finally, we found that the aortas of mice fed a high fat diet had an elevated protein level of PP2APpp2r2d, decreased AMP kinase Thr172 phosphorylation, and contained an Ampk-PP2AP(pp2r2d) complex. Thus, PP2AP(pp2r2d) may antagonize the aortic AMP kinase activity necessary for maintaining normal aortic lipid metabolism. Inhibiting PP2AP(pp2r2d) or activating AMP kinase represents potential pharmacological treatments for many lipid-related diseases. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 02/2015; 290(17). DOI:10.1074/jbc.M114.626259 · 4.60 Impact Factor
  • Atherosclerosis 08/2014; 235(2):e129. DOI:10.1016/j.atherosclerosis.2014.05.358 · 3.97 Impact Factor


Available from