LRP1 Protein Deficiency Exacerbates Palmitate-induced Steatosis and Toxicity in Hepatocytes

Abstract

LRP1 (LDL receptor-related protein-1) is a ubiquitous receptor with both cell signaling and ligand endocytosis properties. In the liver, LRP1 serves as a chylomicron remnant receptor and also participates in the transport of extracellular cathepsin D to the lysosome for prosaposin activation. The current study showed that in comparison with wild type mice, hepatocytespecific LRP1 knock-out (hLrp1 ؊/؊ ) mice were more susceptible to fasting-induced lipid accumulation in the liver. Primary hepatocytes isolated from hLrp1 ؊/؊ mice also accumulated more intracellular lipids and experienced higher levels of endoplasmic reticulum (ER) stress after palmitate treatment compared with similarly treated hLrp1 ؉/؉ hepatocytes. Palmitatetreated hLrp1 ؊/؊ hepatocytes displayed similar LC3-II levels, but the levels of p62 were elevated in comparison with palmitate-treated hLrp1 ؉/؉ hepatocytes, suggesting that the elevated lipid accumulation in LRP1-defective hepatocytes was not due to defects in autophagosome formation but was due to impairment of lipophagic lipid hydrolysis in the lysosome. Additional studies showed increased palmitate-induced oxidative stress, mitochondrial and lysosomal permeability, and cell death in hLrp1 ؊/؊ hepatocytes. Importantly, the elevated cell death and ER stress observed in hLrp1 ؊/؊ hepatocytes were abrogated by E64D treatment, whereas inhibiting ER stress diminished cell death but not lysosomal permeabilization. Taken together, these results documented that LRP1 deficiency in hepatocytes promotes lipid accumulation and lipotoxicity through lysosomalmitochondrial permeabilization and ER stress that ultimately result in cell death. Hence, LRP1 dysfunction may be a major risk factor in fatty liver disease progression.

Low-density lipoprotein receptor–related protein-1 dysfunction synergizes with dietary cholesterol to accelerate steatohepatitis progression

“…4). These data suggested that the Mallory-Denk bodies accumulated in livers of HFHC-fed hLrp1 Ϫ/Ϫ mice could not be explained by changes in autophagy activity but were probably the result of lysosomal defects due to LRP1 deficiency, as we have shown previously (11).…”

“…Nevertheless, plasma triglyceride, nonesterified fatty acids (NEFA), glucose, and insulin levels are similar to those of hLrp1 ϩ/ϩ mice (10). Deficiency of LRP1 in hepatocytes also promotes lipid accumulation and lipotoxicity in response to excessive fatty acids through lysosomal-mitochondrial permeabilization and endoplasmic reticulum stress (11). Thus, mice with liver-specific LRP1 gene deletion (hLrp1 Ϫ/Ϫ mice) exhibited robust dyslipidemia and hepatosteatosis secondary to hepatic insulin resistance when placed on a high-fat diet (12).…”

Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity

“…LRP1 is also critical for lipid transport and metabolism in adipocytes (12,41,42). It improves the hepatic HDL/ LDL secretion ratio (43) and protects hepatocytes from lipotoxic insults (44). Based on these reports in the literature, LRP1 clearly performs unique functions in a cell type-specific way.…”

Hepatic lipophagy: New insights into autophagic catabolism of lipid droplets in the liver

“…For example, liver-specific knockout of low-density lipoprotein receptor-related protein 1 (LRP1) in mice showed that, following a 24-hour fast, a nearly 7-fold increase in hepatic TAG accumulation was observed as compared to wild-type mice. (66) An accumulation of the autophagic cargo adapter p62 was also noted when isolated LRP -/hepatocytes were incubated in the presence of palmitate, suggesting that global autophagy is impaired when this receptor is perturbed. However, no accumulation of LC3 was observed, suggesting that LRP1 is not involved in the biogenesis of autophagic membranes but rather that lysosome-mediated degradation of LDs had been compromised.…”

“…Other factors have recently been shown to participate in the regulation of hepatic lipophagy. For example, liver‐specific knockout of low‐density lipoprotein receptor‐related protein 1 (LRP1) in mice showed that, following a 24‐hour fast, a nearly 7‐fold increase in hepatic TAG accumulation was observed as compared to wild‐type mice . An accumulation of the autophagic cargo adapter p62 was also noted when isolated LRP –/– hepatocytes were incubated in the presence of palmitate, suggesting that global autophagy is impaired when this receptor is perturbed.…”