Figure 9. Proposed mechanisms underlying lipid abnormalities that predict early renal function decline in DKD.

Upregulation of ACC, mediated by insulin resistance, enhances de novo lipogenesis characterized by increased abundance of palmitate, a C16 fatty acid. With elongation and desaturation, palmitate is converted into longer unsaturated fatty acids, which are incorporated into complex lipids (e.g., glycerolipids). In concert, upregulation of ACC also inhibits CPT1, which in turn decreases the conversion of l-carnitine to C16–C20 ACs. C16–C20 ACs are efficient β-oxidation substrates, and, therefore, their diminished mitochondrial transfer downregulates β-oxidation. The net effect of upregulated de novo lipogenesis is characterized by higher abundance of longer chain polyunsaturated glycerolipids and lower abundance of C16–C20 ACs and shorter low-double-bond glycerolipids. ACACA, acetyl-CoA carboxylase alpha; ACLY, ATP citrate lyase; ACS, acetyl-CoA synthetase; CPT, carnitine palmitoyltransferase; DEGS, delta 4-desaturase; ELOVL, elongation of very long chain fatty acids; FASN, fatty acid synthase; FADS, fatty acid desaturase; SCD, stearoyl-CoA desaturase; SLDB TAG, short-low-double-bond triacylglycerol.