Lipid Droplet-Associated Proteins Perilipin 1 and 2: Molecular Markers of Steatosis and Microvesicular Steatotic Foci in Chronic Hepatitis C

Abstract

Chronic infection with hepatitis C (HCV) is a major risk factor in the development of cirrhosis and hepatocellular carcinoma. Lipid metabolism plays a major role in the replication and deposition of HCV at lipid droplets (LDs). We have demonstrated the importance of LD-associated proteins of the perilipin family in steatotic liver diseases. Using a large collection of 231 human liver biopsies with HCV, perilipins 1 and 2 have been localized to LDs of hepatocytes that correlate with the degree of steatosis and specific HCV genotypes, but not significantly with the HCV viral load. Perilipin 1- and 2-positive microvesicular steatotic foci were observed in 36% of HCV liver biopsies, and also in chronic hepatitis B, autoimmune hepatitis and mildly steatotic or normal livers, but less or none were observed in normal livers of younger patients. Microvesicular steatotic foci did not frequently overlap with glycogenotic/clear cell foci as determined by PAS stain in serial sections. Steatotic foci were detected in all liver zones with slight architectural disarrays, as demonstrated by immunohistochemical glutamine synthetase staining of zone three, but without elevated Ki67-proliferation rates. In conclusion, microvesicular steatotic foci are frequently found in chronic viral hepatitis, but the clinical significance of these foci is so far not clear.

Upregulation of Hepatic Glutathione S-Transferase Alpha 1 Ameliorates Metabolic Dysfunction-Associated Steatosis by Degrading Fatty Acid Binding Protein 1

“…Histopathological analysis further revealed that high expression of GSTA1 in mouse livers (Figure 4F, GSTA1) reduced steatosis, hepatocellular ballooning, and lobular inflammation, which was confirmed by the decreased NAS score (Figure 4F). The results were also confirmed by Western blot analysis, which showed a higher level of GSTA1 and lower levels of DGAT2 and PLIN2 (Figure 4G), two markers of LD accumulation [18,21], agreeing with our results in cells (Figure 3A,B). These results hint that a high level of GSTA1 ameliorates the accumulation of LD, thereby preventing the occurrence and progression of liver steatosis to MASLD.…”

“…The results showed that the expression of GSTA1 was lower in the livers of patients with MASLD than in healthy individuals (Figure 2C). In the livers of mice fed HFD for 12 weeks, Western diet (WD) for 16 weeks, or WD/CCl 4 for 12 and 24 weeks, the expression of GSTA1 was inversely related to the level of perilipin 2 (PLIN2) (Figure 2D), which is one of the constitutively and ubiquitously expressed proteins homing to the lipid droplets and was used as a protein marker for lipid droplets [18,19]. These results demonstrate that GSTA1 expression is negatively associated with the accumulation of LD and might be a protective factor for the progression of MASLD.…”

Review article: Hepatic steatosis and its associations with acute and chronic liver diseases

“…Hepatitis C virus (HCV) exhibits dependence on hepatocellular LDs for replication and itself induces LD formation. Classically, chronic infection by genotype 3 57,145,146 or 3a 147 is associated most strongly with hepatic steatosis, and viral load correlates with steatosis grade in the case of genotype 3 148 . The core protein of HCV includes, in its second domain (D2), two alpha helices joined by a hydrophobic loop containing proline residues at positions 138 and 143 analogous to the proline knot within oleosin plant LD proteins 149,150 .…”

Chronic Liver Disease: Latest Research in Pathogenesis, Detection and Treatment

“…Regarding the steatotic situation that characterizes CLDs, including NAFLD/NASH and HCV, a relevant role is played by the pathologic accumulation of micro- or macrovesicular lipid droplets (LDs) in hepatocytes. Concerning this, a study by Schelbert et al [ 9 ] demonstrated the importance of LD-associated proteins of the perilipin family in steatotic liver diseases. Using a large collection of human liver biopsies with HCV of different grades and stages, they showed that perilipins 1 and 2 localized to LDs of hepatocytes, correlating with the degree of steatosis and specific HCV genotypes, but not significantly with the HCV viral load.…”