Background: The challenge of high-fat diet lipotoxicity
A sustained high-fat diet (HFD) can drive metabolic derangements that disproportionately affect the liver. Lipotoxicity from excess fatty acids and lipid intermediates promotes hepatic steatosis, liver injury, and inflammation, contributing to metabolic diseases such as non-alcoholic fatty liver disease (NAFLD). Understanding the dynamic effects of HFD on liver lipid metabolism and identifying protective strategies are essential for improving metabolic health.
Objectives: Mapping lipotoxic processes and testing Ganoderma lucidum
The study aimed to (1) chart how a 45%–60% HFD alters lipid handling and liver pathology over time in mice, (2) uncover the molecular mechanisms of hepatic lipotoxicity—focusing on inflammatory signaling, unfolded protein response (UPR), and ER-phagy—and (3) evaluate whether Ganoderma lucidum extract (GLE) can mitigate lipotoxicity both in cultured hepatocytes and in live mice receiving an HFD.
Methods: A multi-model approach
Young adult C57BL/6 mice were placed on either a 45% or 60% HFD, with assessments at four, eight, twelve, and sixteen weeks. Researchers measured body composition, serum lipids, and liver pathology. At 16 weeks, inflammatory signaling (including STING and NF-κB), UPR branches (PERK and IRE1), and ER-phagy receptors were analyzed, highlighting compensatory liver responses. In a parallel set of experiments, male mice were divided into four groups (n = 12 per group): normal diet, 45% HFD, and two HFD groups receiving Ganoderma lucidum water extract (GLE) at 1 g/kg/d or 2 g/kg/d via gavage for eight weeks after a four-week HFD induction. Primary hepatocytes were used to examine GLE’s effects on palmitic acid–induced lipotoxicity in vitro.
Key findings: Lipotoxicity with inflammation and adaptive responses
HFD induced progressive increases in body weight, fat mass, serum lipids, and hepatic steatosis. Glucose tolerance deteriorated and liver injury markers—alanine aminotransferase (ALT) and aspartate aminotransferase (AST)—rose, signaling hepatocellular stress. The lipotoxic state activated inflammatory pathways, notably STING and NF-κB, and triggered UPR, with both PERK and IRE1 branches engaged. Additionally, ER-phagy receptors, particularly FAM134B, were upregulated in hepatocytes after prolonged HFD, suggesting a cellular attempt to manage ER stress and maintain proteostasis. These responses reflect a coordinated attempt to cope with lipid-induced damage while revealing potential targets for intervention.
In vitro protection by Ganoderma lucidum
GLE significantly mitigated palmitic acid–induced lipotoxicity in primary hepatocytes: cell viability improved, and culture supernatants showed lower ALT, AST, and lactate dehydrogenase (LDH) levels. TUNEL staining indicated fewer apoptotic cells with GLE treatment, aligning with reduced hepatocyte injury at the cellular level.
In vivo protection by Ganoderma lucidum
Among 45% HFD-fed mice, GLE supplementation lowered serum total cholesterol and LDL-cholesterol and reduced hepatic triglyceride content, indicating improved lipid handling and liver health. The higher-dose GLE group showed benefits consistent with dose-dependent activity, underscoring GLE’s potential to support metabolic resilience under lipotoxic stress.
Mechanisms: A balanced response to lipotoxic stress
Results point to a protective mechanism where Ganoderma lucidum helps orchestrate the liver’s compensatory responses. By modulating the UPR and ER-phagy in a coordinated manner, GLE may reduce ER stress and limit inflammatory signaling while preserving hepatocyte viability. The attenuation of STING and NF-κB pathways further suggests a dampening of inflammation, contributing to improved liver function during HFD exposure.
Implications: Ganoderma lucidum as a dietary strategy for metabolic health
These findings support Ganoderma lucidum as a promising dietary supplement to help manage lipotoxicity-associated liver injury and metabolic disturbances. While the research is preclinical, the complementary in vitro and in vivo data highlight a potential role for GLE in protecting hepatic health during high-fat dietary challenges. Further studies in humans are needed to evaluate optimal dosing, safety, and long-term benefits in metabolic disease contexts.
Future directions
Future work should explore the precise molecular interactions between GLE and UPR/ER-phagy regulators, assess combinational strategies with other dietary interventions, and determine whether GLE’s hepatoprotective effects extend to diverse dietary compositions and genetic backgrounds.
