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FB2026_01
,
released March 12, 2026
In response to starvation, cells in the human liver (hepatocytes) accumulate numerous lipid droplets, resulting in hepatic steatosis. This condition is described as metabolic dysfunction-associated steatotic liver disease (MASLD) or non-alcoholic fatty liver disease (NAFLD). Low-protein diets can also result in MASLD. Drosophila larval oenocytes, functionally analogous to hepatocytes, accumulate numerous lipid droplets during starvation in a process resembling starvation-induced hepatic steatosis; the observed phenotypes of hepatic steatosis are reversible upon resumption of feeding.
This Drosophila system has been used to characterize genes and molecular mechanisms involved in hepatic steatosis. The levels of Dmel\Lsd-2 (ortholgous to human PLIN2) in oenocytes increases significantly under starvation conditions. In all feeding conditions, the protein level of Lsd-2 in oenocytes is found to correlate with lipid content. Oenocyte-specific knockdown of Lsd-2, mediated by RNAi, prevents starvation-induced steatosis.
Oenocyte-specific knockdown of Dmel\Fatp2, mediated by RNAi, also prevents starvation-induced steatosis. Fatp2 is orthologous to several human genes encoding fatty acid transporters, including SLC27A2, SLC27A4, SLC27A1, and SLC27A3. Work in vertebrates implicates SLC27A2 in the initiation of starvation-induced hepatic steatosis.
The E3 ubiquitin ligase Dmel\Ubr1 (orthologous to human UBR1 and UBR2) was identified as regulating Lsd-2 ubiquitination and subsequent degradation. Reduced levels of Ubr1 in oenocytes results in phenotypes characteristic of hepatic steatosis; these phenotypes are reversed upon oenocyte-specific knockdown of Lsd-2. Using S2 cells, it was determined that the Lsd-2-Ubr1 protein interaction is stimulated by essential amino acids, especially leucine and isoleucine.
[updated Jul. 2024 by FlyBase; FBrf0222196]
The accumulation of excess triglyceride in the liver, a condition known as hepatic steatosis (or fatty liver), is associated with adverse metabolic consequences including insulin resistance and dyslipidemia. Factors promoting deposition of fat in the liver include obesity, diabetes, insulin resistance, and alcohol ingestion. Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease in Western countries. In a subset of individuals hepatic steatosis promotes an inflammatory response in the liver, referred to as steatohepatitis, which can progress to cirrhosis and liver cancer (summary by Romeo et al., 2008, pubmed:18820647). [from MIM:613282; 2022.05.08]
Several genes with variants conferring susceptibility to NAFLD have been tentatively identified: PNPLA3 (MIM:613282) and APOC3 (MIM:613387).
Nonalcoholic fatty liver disease (NAFLD), also known as nonalcoholic hepatic steatosis, is characterized by hepatic lipid droplet (LD) accumulation. Malnutrition, specifically a low-protein diet, can promote the pathogenesis of NAFLD (FBrf0253285 and references cited therein).
UBR1 and UBR2 encode E3 ubiquitin ligases of the N-end rule proteolytic pathway that targets proteins for polyubiquitylation and proteasome-mediated degradation. [Gene Cards, UBR2, UBR1; 2022.05.08]
PLIN2 encodes a member of the perilipin family, members of which coat intracellular lipid storage droplets; it is involved in development and maintenance of adipose tissue, but is also found in other tissue and cell types, including hepatocytes. [Gene Cards, PLIN2; 2022.05.08]
Many to one: 2 human genes to 1 Drosophila gene.
Many to one: multiple human genes to 1 Drosophila gene.
Many to one: 2 human genes to 1 Drosophila gene.
Many to many: 4 human genes to 3 Drosophila genes.
High-scoring ortholog of human UBR1 and UBR2 (1 Drosophila to 2 human).
Moderate-scoring ortholog of human PLIN2; lower-scoring ortholog of human PLIN1, PLIN3, PLIN4, PLIN5 (1 Drosophila to multiple human).