What is the Pathophysiology of Elevated Plasma FFAs

Plasma FFA concentration reflects a balance between release (by the intravascular lipolysis of triglyceride-rich lipoproteins and lipolysis of predominantly adipose tissue triglyceride stores) and tissue uptake (predominantly re-esterified in adipose tissue and liver and oxidized in muscle, heart, and liver). In the postabsorptive state, the systemic FFA concentration is determined largely by the rate of FFA entry into the circulation, but postprandially the rate of uptake/esterification, particularly by adipose tissue, is also a critical determinant of plasma FFA concentration (Fig. 2 and Color Plate 3, following p. 34).

Enhanced Adipose Tissue Lipolysis (Fig. 2 and Color Plate 3, following p. 34)

Lipolysis (hydrolysis) of adipose tissue TG stores mobilizes energy by releasing FFAs and glycerol into the circulation, to be utilized by other tissues. The lipolytic process, as assessed by circulating levels of FFAs and glycerol, displays diurnal variability (41,42). Until very recently, the hydrolysis of TG within the adipocyte was

Adipocyte Lipolysis And Circulatory Ffa

Fig. 2. Control of fatty acid uptake and release by adipose tissue. Insulin promotes FFA uptake into the adipocyte by stimulating the LPL-mediated release of FFA from lipoprotein triglyceride (1). Fatty acids enter the adipocyte both by diffusion down a concentration gradient as well as by facilitated transport by fatty acid transporters (2). Insulin also stimulates glucose transport into the adipocyte, thereby increasing the availability of glycerol-3P for triglyceride synthesis (3). Insulin may have a direct stimulatory effect on lipogenic enzymes such as DGAT (4). By inhibiting HSL and ATGL (5), it reduces the intracellular lipolysis of cytosolic triglycerides, thereby promoting adipocyte triglyceride storage. Parasympathetic output from the brain may inhibit lipolysis directly (6). ASP (7), whose action is complementary to that of insulin in the adipocyte, stimulates glucose uptake and fatty acid esterification and inhibits mobilization of stored triglycerides. Defective adipose tissue trapping and esterification or enhanced lipolysis of stored triglycerides as occurs in insulin resistance would result in elevated FFA flux from adipose to non-adipose tissue. Abbreviations are: ACS, acylCoA synthase, ASP = acylation stimulating protein, FFA-Alb = albumin bounded fatty acid, CM = chylomicron, DGAT = diacylglycerol acyltransferase, FFA = free (nonesterified) fatty acid, FA = fatty acid, FATP = fatty acid transport protein, GLUT = glucose transporter, Glycerol-3P = glycerol-3 phosphate, DAG = diacylglycerol, HSL = hormone sensitive lipase, LPL = lipoprotein lipase, TG = triglyceride, VLDL = very low density lipoprotein. Solid lines indicate flux of metabolic substrates and dashed lines indiated stimulatory or inhibitory effects of insulin. '+' indicates a stimulatory effect of insulin and "-" indicates an inhibitory effect of insulin (see Color Plate 3, following p. 34).

Fig. 2. Control of fatty acid uptake and release by adipose tissue. Insulin promotes FFA uptake into the adipocyte by stimulating the LPL-mediated release of FFA from lipoprotein triglyceride (1). Fatty acids enter the adipocyte both by diffusion down a concentration gradient as well as by facilitated transport by fatty acid transporters (2). Insulin also stimulates glucose transport into the adipocyte, thereby increasing the availability of glycerol-3P for triglyceride synthesis (3). Insulin may have a direct stimulatory effect on lipogenic enzymes such as DGAT (4). By inhibiting HSL and ATGL (5), it reduces the intracellular lipolysis of cytosolic triglycerides, thereby promoting adipocyte triglyceride storage. Parasympathetic output from the brain may inhibit lipolysis directly (6). ASP (7), whose action is complementary to that of insulin in the adipocyte, stimulates glucose uptake and fatty acid esterification and inhibits mobilization of stored triglycerides. Defective adipose tissue trapping and esterification or enhanced lipolysis of stored triglycerides as occurs in insulin resistance would result in elevated FFA flux from adipose to non-adipose tissue. Abbreviations are: ACS, acylCoA synthase, ASP = acylation stimulating protein, FFA-Alb = albumin bounded fatty acid, CM = chylomicron, DGAT = diacylglycerol acyltransferase, FFA = free (nonesterified) fatty acid, FA = fatty acid, FATP = fatty acid transport protein, GLUT = glucose transporter, Glycerol-3P = glycerol-3 phosphate, DAG = diacylglycerol, HSL = hormone sensitive lipase, LPL = lipoprotein lipase, TG = triglyceride, VLDL = very low density lipoprotein. Solid lines indicate flux of metabolic substrates and dashed lines indiated stimulatory or inhibitory effects of insulin. '+' indicates a stimulatory effect of insulin and "-" indicates an inhibitory effect of insulin (see Color Plate 3, following p. 34).

thought to be catalyzed mainly by hormone sensitive lipase (HSL). Hormones with lipolytic activity such as glucagon and catecholamines activate HSL by phosphorylation via cAMP-mediated activation of PKA, whereas the major antilipolytic hormone, insulin, exerts a strong suppressive effect on HSL activation. HSL-mediated lipolysis requires caveolin-1-facilitated PKA phosphorylation of a protein named perilipin A, present at the surface of lipid storage droplets. Perilipin A phosphorylation allows HSL to gain access to the surface of lipid droplets, to participate in lipolysis of stored triglycerides (43,44). A number of studies have shown a diminished suppressive effect of insulin on the rate of appearance of FFA in obese and nonobese insulin resistant humans (45,46). Resistance to insulin's suppressive effect on HSL also appears to be present postprandially in insulin resistance and type 2 diabetes (47). Although the diminished whole body insulin suppressive effect on FFA rate of appearance seen in insulin resistant individuals has readily been assumed to be owing to resistance to insulin suppression of HSL, HSL is normally exquisitely sensitive to the suppressive effects of insulin, and it is not clear how important this mechanism is in individuals whose peripheral tissue insulin concentrations are generally elevated. The mass effect of FFA released from expanded body fat depots may also play an important role. A number of in vitro studies have in fact failed to demonstrate either increased HSL activity and basal lipolytic rate in adipose tissue from obese individuals or resistance to insulin's suppressive effect on HSL (48).

An important clue to the existence of other adipose tissue lipase enzymes came from studies of mice lacking HSL, because they have normal body weight and reduced, not increased, fat mass (49-51), and exhibit accumulation of diacylglycerol (DAG) in fat cells (52). In addition, HSL-deficient mice showed that HSL-independent lipolysis is increased upon fasting (53). These data suggested that at least one other unidentified lipase exists, which is presumably responsible for the hydrolysis of TG into DAG, the latter being the main substrate for HSL. Indeed, Zechner and collaborators recently discovered a new lipase that is highly expressed in adipose tissue, which they named "adipose triglyceride lipase" (ATGL) (54). ATGL initiates the hydrolysis of TG, generating DAGs and FAs. Lipases identified at more or less the same time by Villena et al., and Jenkins et al., called desnutrin and the calcium-dependent phospholipase iPLA2£ respectively, were later found to be identical to ATGL (36,55). ATGL associates with lipid droplets, and is under the control of hormonal regulation by glucocorticoids (upregulation) and insulin (downregulation), and its expression is reduced in a mouse model of obesity. It is likely that ATGL is responsible for lipolysis in HSL-deficient mice, although other lipases may contribute to the process. Indeed, a recent report shows that overexpression of ATGL in vitro in the 3T3-L1 cell increases basal and isoproterenol-stimulated release of FFAs and glycerol, whereas siRNA-mediated knock down of ATGL resulted in the opposite effect (56). Consistent with its suppression by insulin, ATGL expression was increased in adipose tissue from diabetic insulinopenic streptozotocin-treated mice or in adipose-specific insulin receptor-deficient mice (56). ATGL and HSL therefore appear to function in a co-ordinated fashion to mobilize stored adipose tissue triglycerides, with ATGL acting mainly as a triglyceride lipase, whereas HSL acts primarily at the next step, that of diglyceride lipolysis. Exactly how these two key adipose tissue lipolytic enzymes co-ordinate their actions and their differential regulation by hormones and other factors has not yet been established.

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Responses

  • christina
    What transports into adipocytes and is stored as tg glucose?
    6 years ago
  • Shawn
    What is the Pathophysiology of Elevated Plasma FFAs?
    6 years ago

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