Diet-derived and diet-related endogenously produced palmitic acid: Effects on metabolic regulation and cardiovascular disease risk

Abstract

Palmitic acid is the predominant dietary saturated fatty acid (SFA) in the US diet. Plasma palmitic acid is derived from dietary fat and also endogenously from de novo lipogenesis (DNL) and lipolysis. DNL is affected by excess energy intake resulting in overweight and obesity, and the macronutrient profile of the diet. A low-fat diet (higher carbohydrate and/or protein) promotes palmitic acid synthesis in adipocytes and the liver. A high-fat diet is another source of palmitic acid that is taken up by adipose tissue, liver, heart and skeletal muscle via lipolytic mechanisms. Moreover, overweight/obesity and accompanying insulin resistance increase non-esterified fatty acid (NEFA) production. Palmitic acid may affect cardiovascular disease (CVD) risk via mechanisms beyond increasing low-density lipoprotein-cholesterol (LDL-C), notably synthesis of ceramides and possibly through branched fatty acid esters of hydroxy fatty acids (FAHFAs) from palmitic acid. Ceramides are positively associated with incident CVD, whereas the role of FAHFAs is uncertain. Given the new evidence about dietary regulation of palmitic acid metabolism there is interest in learning more about how diet modulates circulating palmitic acid concentrations and, hence, potentially CVD risk. This is important because of the heightened interest in low carbohydrate (carbohydrate controlled) and high carbohydrate (low-fat) diets coupled with the ongoing overweight/obesity epidemic, all of which can increase plasma palmitic acid levels by different mechanisms. Consequently, learning more about palmitic acid biochemistry, trafficking and how its metabolites affect CVD risk will inform future dietary guidance to further lower the burden of CVD.

Keywords: CVD risk; Ceramides; Diet-derived; Endogenous synthesis; FAHFAs; Palmitic acid.

Figure 1.

Proposed Mechanisms by which Circulating Palmitic Acid from Diet-Derived and Diet-Related Endogenously Produced Palmitic Acid Modulate Metabolic Events that may Promote Atherosclerosis. Chronic energy surplus is associated with increased weight, increased liver fat, and insulin resistance. In this context, increased carbohydrate intake drives increased de novo lipogenesis (DNL) in the liver and increased fat intake (specifically from saturated fatty acids (SFA)) drives increased intracellular lipolysis in the adipose tissue. Overfeeding with SFA leads to increased palmitic acid-derived ceramides, but subsequent markers of inflammation or oxidative stress have not been consistently measured in overfeeding studies. Various dietary patterns in the absence of weight gain lead to increased circulating palmitic acid especially when SFAs are the predominant type of fat. Moreover, two studies examining isocaloric diets with increased SFA [74] and decreased fructose [75] support the pathway for ceramide production or reduction, respectively. ¹Average American Intake (diets high in SFA, sodium, added sugars, including fructose, and low in fiber) [1], ²Low carbohydrate intake (high fat/SFA diet) [76], ³High carbohydrate intake (refined carbohydrates and added sugars, including fructose) [27, 39]. FAHFA: fatty acid esters of hydroxy fatty acids; CM: chylomicron; VLDL: very low-density lipoproteins.

Figure 2.

Dietary and Endogenous Palmitic Acid Metabolism. Dietary palmitic acid is emulsified and hydrolyzed in the duodenum to become a free fatty acid (FFA) or monoacylglycerol (MAG), which can be absorbed by enterocytes. FFA and MAG are re-esterified into triglycerides (TG) in the cytosol and incorporated into chylomicrons (CM) and transported into a lymph duct for transport to the rest of the body. Lipoprotein lipase (LpL) on extra-hepatic tissues hydrolyze the CM to release FFA from the TG to produce a CM-remnant (CM-R). In the fed state, increased glucose leads to insulin secretion that stimulates GLUT4 and CD36 translocation to the plasma membrane facilitating uptake of glucose and palmitic acid into the adipocyte. Glucose is metabolized to pyruvate, which enters the TCA cycle and produces citrate and subsequently acetyl-CoA. De novo lipogenesis utilizes the acetyl-CoA to synthesize palmitic acid, the primary product of FAS. Palmitic acid can be used as a precursor for FAHFA and ceramide synthesis and have downstream effects as discussed in the paper. ¹Average American Intake (diets high in SFA, sodium, added sugar s including fructose and low in fiber [1], ²Low carbohydrate intake (high fat/SFA diet) [76], ³High carbohydrate intake (refined carbohydrates and added sugars including fructose) [27, 39]. DAG: diacylglycerol, MGL: monoacylglycerol lipase, HSL: hormone sensitive lipase, ATGL: adipose triglyceride lipase