Role of Different Dietary Saturated Fatty Acids for Cardiometabolic Risk

David Iggman; Ulf Risérus


Clin Lipidology. 2011;6(2):209-223. 

In This Article


Cellular Effects

Besides the traditional view that dietary SFA (when considered as a group) can decrease membrane fluidity in the cells where they are deposited and thus affect an array of metabolic pathways; SFA have been shown to induce a proinflammatory gene expression pattern in adipose tissue.[10] Such effects may also be linked to the accumulation of diacylglycerol and ceramide, to increased activation of NF-κB, PKC and MAPK, which leads to induction of inflammatory genes. The synthesis of ceramide can induce apoptosis.[11,12] In addition, much interest has been placed on the receptor family termed Toll-like receptors (TLRs), hypothesized to be a link between fat, inflammation and insulin resistance.[13] SFA have been postulated to act as ligands, especially for TLR 4 and possibly also TLR 2. For TLR 4, this has mostly been demonstrated with 12:0 as the ligand, but also with 16:0.[14] However, in another study the observed effects on TLR and inflammation have instead been considered to represent contamination with lipopolysaccharides of bovine serum antigen, rather than a true effect of SFA.[15]

Insulin Resistance & Pancreatic Dysfunction

Circulating SFA, particularly 16:0 as nonesterified fatty acids (NEFA), has been demonstrated to promote insulin resistance by decreasing phosphorylation of the insulin receptor and insulin receptor substrate-1, thereby affecting cell signaling.[16] SFA (mostly demonstrated for 16:0) may also decrease oxidation of fatty acids and glucose in muscle cells, which elevates these levels in tissues and blood, and decreases adiponectin production, which may both promote insulin resistance. These mechanisms have recently been described in detail by Kennedy et al..[17] Besides insulin resistance in peripheral tissues (mainly skeletal muscle but also adipose tissue), fatty liver and hepatic insulin resistance is increasingly prevalent. This is of relevance as the other main aspect of insulin action is to suppress glucose production by the liver. Disturbed intracellular fatty acid metabolism may lead to excessive accumulation of TGs, subsequent oxidation of fatty acids, and cellular injury.[18] Another interrelated, distinct pathway to the development of diabetes is via disruption of β-cell function. The SFA 16:0 and 14:0 have been demonstrated to stimulate β-cells in a glucose-like fashion,[19] as postulated in the lipotoxicity hypothesis.[20] As SFA TG content (especially 16:0 since it is a precursor to ceramide) in pancreatic islets increases, nitric oxide and ceramide are synthesized, which may result in lipotoxic effects, including increased oxidative stress, inflammation and endoplasmic reticulum (ER) stress, and lead to β-cell apoptosis.[21] Simultaneously, insulin gene expression is inhibited.[22] The mechanisms of NEFA on β-cell dysfunction have been described in more detail elsewhere.[23,24]

Circulating Lipids

The existence of desaturases (e.g., SCD) may be a metabolic means to avoid excessive levels of circulating 16:0 and 18:0.[25] Increased SFA intake has been associated with increased SCD-1 activity in humans,[7] which may predict mortality.[26] Interestingly, in obese mice disruption of the SCD-1 gene improves cardiac function.[27] In the human liver, SCD-1 can contribute to the synthesis of cholesteryl oleate from dietary or endogenous SFA including 16:0 and 18:0, which has been proposed to promote atherosclerosis via formation of foam cells.[28] Finally, one mechanism through which SFA and TFA raise serum cholesterol was described in 2005 by Lin et al..[29] High SFA intake stimulates the coactivator PGC-1β and transcription factors of the sterol regulatory element binding protein (SREBP) 1c and 1a in the liver, stimulating lipogenic gene expression. Specifically, 16:0 was active in inducing PGC-1β in hepatocytes, as were other MC and LC SFA, as well as TFA (including dairy TFA). In addition, PGC-1β decreases fat accumulation in the liver while simultaneously increasing circulating VLDLs.[29]