The Propensity of the Human Liver to Form Large Lipid Droplets Is Associated with PNPLA3 Polymorphism, Reduced INSIG1 and NPC1L1 Expression and Increased Fibrogenetic Capacity

Abstract

In nonalcoholic steatohepatitis animal models, an increased lipid droplet size in hepatocytes is associated with fibrogenesis. Hepatocytes with large droplet (Ld-MaS) or small droplet (Sd-MaS) macrovesicular steatosis may coexist in the human liver, but the factors associated with the predominance of one type over the other, including hepatic fibrogenic capacity, are unknown. In pre-ischemic liver biopsies from 225 consecutive liver transplant donors, we retrospectively counted hepatocytes with Ld-MaS and Sd-MaS and defined the predominant type of steatosis as involving ≥50% of steatotic hepatocytes. We analyzed a donor Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism, hepatic expression of proteins involved in lipid metabolism by RT-PCR, hepatic stellate cell (HSC) activation by α-SMA immunohistochemistry and, one year after transplantation, histological progression of fibrosis due to Hepatitis C Virus (HCV) recurrence. Seventy-four livers had no steatosis, and there were 98 and 53 with predominant Ld-MaS and Sd-MaS, respectively. In linear regression models, adjusted for many donor variables, the percentage of steatotic hepatocytes affected by Ld-MaS was inversely associated with hepatic expression of Insulin Induced Gene 1 (INSIG-1) and Niemann-Pick C1-Like 1 gene (NPC1L1) and directly with donor PNPLA3 variant M, HSC activation and progression of post-transplant fibrosis. In humans, Ld-MaS formation by hepatocytes is associated with abnormal PNPLA3-mediated lipolysis, downregulation of both the intracellular cholesterol sensor and cholesterol reabsorption from bile and increased hepatic fibrogenesis.

An Egg White-Derived Peptide Enhances Systemic Insulin Sensitivity and Modulates Markers of Non-Alcoholic Fatty Liver Disease in Obese, Insulin Resistant Mice

“…In NAFLD, progression to NASH is characterized by increased LD size, hepatocyte hypertrophy and inflammation [ 2 , 5 ]. Surprisingly, the ROSI group exhibited a true microvesicular steatosis mixed with macrovesicular steatosis, while PEP2 and HFD groups appeared to have macrovesicular steatosis, which is considered more pathological [ 20 , 21 , 22 ]. However, PEP2 tended to decrease LD area compared to HFD.…”

“…Therefore, PEP2 group presented a macrovesicular steatosis with small LD vs. macrovesicular steatosis with large LD in the HFD group. The importance of LD size is highlighted by findings showing that macrovesicular steatosis is linked to fibrosis and microcirculation impairment in rodents [ 31 , 32 ] and fibrogenesis in humans [ 20 ]. Moreover, the extent of macrovesicular steatosis can impact liver transplantation and graft survival in humans [ 21 ].…”

“…In terms of LD size, there is not a defined numerical threshold for small or large LD categories. However, based on the literature, hepatic lipid accumulation was divided into three categories, macrovesicular with one large LD displacing the nucleus to the side, macrovesicular with one single small LD not displacing the nucleus and true microvesicular steatosis where several small LD occupy a hepatocyte, giving it a foamy appearance [ 20 , 21 , 22 ].…”

Multi-Omics Integration Analysis Identifies Lipid Disorder of a Non-Alcoholic Fatty Liver Disease (NAFLD) Mouse Model Improved by Zexie–Baizhu Decoction

“…But, the ZXBZ-L group had generally fewer large lipid droplets than the vehicle group ( Figure 2F ). Many previous studies demonstrated that the larger size of lipid droplets would make more serious hepatocyte injuries ( Ferri et al, 2021 ; Mashek, 2021 ). Therefore, we speculated that the low dosage of ZXBZ decoction could protect livers by reducing the formation of large hepatic lipid droplets and increasing the PGC-1α expression.…”

Hepatic patatin‐like phospholipase domain‐containing 3 levels are increased in I148M risk allele carriers and correlate with NAFLD in humans

“…The hepatic lipid content and size of the lipid droplets were also larger in PNPLA3 148M risk allele carriers, which is in accordance with an earlier finding linking large lipid droplets to PNPLA3 148M carriers. [ 34 ] Recently, a small study in 26 patients with NAFLD, using another antibody, found that PNPLA3 was predominantly expressed in hepatic stellate cells and was elevated in PNPLA3 148M carriers. [ 35 ] Although the cellular localization of PNPLA3 in that study differs from both our study and from that in Donati et al, [ 33 ] it indicates that hepatic PNPLA3 levels may also be associated with liver fibrosis in patients with more advanced liver disease.…”