Abstract
Knockdown of patatin-like phospholipase domain-containing protein 3 (PNPLA3) increased triglycerides (TG) in primary bovine hepatocytes, suggesting that PNPLA3 plays a causal role in hepatic TG clearing. In vivo, PNPLA3 abundance across the periparturient period is inversely related to hepatic TG accumulation and circulating fatty acid (FA) concentrations. The purpose of this research was to determine if PNPLA3, as well as other lipases, transcription factors, or FA-mediated genes, are regulated by FA mimicking liver lipid accumulation (ACCUM) and liver lipid clearing (RECOV) or singular FA physiologically found in dairy cows at 0.5 mM of circulating RECOV (iRECOV). Abundance of PNPLA3 tended to decrease with ACCUM and increased quadratically with RECOV (P ≤ 0.10), differing from PNPLA3 expression, but consistent with previous in vivo research. Adipose TG lipase abundance, but not other lipase abundances, was quadratically responsive to both ACCUM and RECOV (P ≤ 0.005). Abundance of PNPLA3 and SREBP1c and expression of LXRA responded similarly to iRECOV, with C18:0 tending to decrease abundance (P ≤ 0.07). Results indicate that bovine PNPLA3 is translationally regulated by FA and although a LXRA-SREBP1c pathway mediation is possible, the mechanism warrants further investigation.
Highlights
Knockdown of patatin-like phospholipase domain-containing protein 3 (PNPLA3) increased triglycerides (TG) in primary bovine hepatocytes, suggesting that PNPLA3 plays a causal role in hepatic TG clearing
The objectives of this study were to 1) determine how PNPLA3 responds to fatty acid (FA) presented in mixtures representing two distinct phases of the periparturient period [period of liver lipid accumulation (ACCUM) or period of liver lipid clearing (RECOV)], 2) determine if potential responses to FA mixtures can be attributed to individual FA [concentration of individual FA physiologically found in dairy cows present in circulating serum at 0.5 mM], and 3) determine potential regulation of PNPLA3 through a targeted analysis of genes and proteins associated with lipolysis and FA-mediation
C18:1 n-9 and C18:2 n-6 are found in lower concentration in recovery from fatty liver (RECOV) than ACCUM and both resulted in increased PNPLA3 abundance compared with C18:0 and maintained abundance compared with C14:0 and C16:0 (Fig. 7). These findings suggest that C18:1 n-9 and C18:2 n-6 could be inhibiting PNPLA3 abundance, as evidenced by the decreased abundance during treatment with ACCUM but increased abundance with RECOV and exposure to iRECOV
Summary
Knockdown of patatin-like phospholipase domain-containing protein 3 (PNPLA3) increased triglycerides (TG) in primary bovine hepatocytes, suggesting that PNPLA3 plays a causal role in hepatic TG clearing. An in vivo study elucidated that periparturient dairy cows with more hepatic PNPLA3 abundance had lower hepatic TG12 In conjunction with those findings, knockdown of PNPLA3 abundance using siRNA in primary bovine hepatocytes resulted in greater cellular TG content compared to cells treated with a nonspecific siRNA sequence[12]. The objectives of this study were to 1) determine how PNPLA3 responds to FA presented in mixtures representing two distinct phases of the periparturient period [period of liver lipid accumulation (ACCUM) or period of liver lipid clearing (RECOV)], 2) determine if potential responses to FA mixtures can be attributed to individual FA [concentration of individual FA physiologically found in dairy cows present in circulating serum at 0.5 mM (iRECOV)], and 3) determine potential regulation of PNPLA3 through a targeted analysis of genes and proteins associated with lipolysis and FA-mediation
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