Research
Mixed
Systemic insulin resistance drives hepatic steatosis in NAFLD by increasing adipose lipolysis and hepatic de novo lipogenesis, while specific saturated fatty acids (like palmitate) cause lipotoxicity, ER stress, and hepatocyte apoptosis, which triggers innate and adaptive immune responses leading to NASH and fibrosis.
NAFLD/NASH is driven by insulin resistance and toxic lipid accumulation (lipotoxicity), not just 'fat in the liver.' Managing insulin sensitivity and reducing saturated fat intake may help, but genetic factors and immune system activation also play critical roles in progression to liver damage.
GoodSupportsHIGH confidence
Systemic insulin resistance is a major driver of hepatic steatosis in NAFLD. Lipotoxicity of accumulated lipids along with activation of the innate immune system are major drivers of NASH. Lipid-induced sublethal and lethal stress culminates in the activation of inflammatory processes... Innate and adaptive immune mechanisms... are central drivers of inflammation that recognize damage- and pathogen-associated molecular patterns and contribute to the progression of the inflammatory cascade.
Why this rating
Review of multiple human and animal studies, multiomics, and genetic data; high quality but observational/mechanistic.
Source
Pathogenesis of Nonalcoholic Steatohepatitis: An Overview
Gopanandan Parthasarathy et al. · Hepatology Communications · 2020
DOI 10.1002/hep4.1479
narrative_reviewCited 421×
Read the paper DOI resolved against Crossref · corpus check 2026-06-10
More from this paper
- Saturated fatty acids, particularly palmitate, induce hepatocyte apoptosis via ER stress, JNK activation, and death receptor pathways, while monounsaturated fatty acids (MUFAs) like oleate can be cytoprotective by sequestering palmitate into neutral triglycerides.Good
- Innate and adaptive immune cells (Kupffer cells, monocytes, neutrophils, T cells) are central drivers of NASH inflammation and fibrosis, with specific pathways like NLRP3 inflammasome activation and CCL2/CCR2 monocyte recruitment being critical for disease progression.Good
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