Lipid Accumulation and Insulin Resistance: Bridging Metabolic Dysfunction-Associated Fatty Liver Disease and Chronic Kidney Disease

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD), a recently proposed term to replace non-alcoholic fatty liver disease (NAFLD), emphasizes the critical role of metabolic dysfunction and applies broader diagnostic criteria. Diagnosis of MAFLD requires evidence of hepatic steatosis combined with obesity, type 2 diabetes mellitus, or other metabolic dysregulation conditions, all of which significantly elevate the risk of chronic kidney disease (CKD). This review discusses the pathological mechanisms of lipid accumulation and insulin resistance in MAFLD and CKD, highlighting their mechanistic connections. Specifically, ectopic fat accumulation triggered by metabolic reprogramming, oxidative stress and inflammation induced by energy overload, modified lipids, uremic toxins, and senescence, as well as insulin resistance pathways activated by pro-inflammatory factors and lipotoxic products, collectively exacerbate simultaneous hepatic and renal injury. Moreover, interactions among hyperinsulinemia, the sympathetic nervous system, the renin-angiotensin system (RAS), and altered adipokine and hepatokine profiles further amplify insulin resistance, ectopic lipid deposition, and systemic damage. Finally, the review explores potential therapeutic strategies targeting lipid metabolism, insulin sensitivity, and RAS activity, which offer promise for dual-organ protection and improved outcomes in both hepatic and renal systems.

Keywords: chronic kidney disease; insulin resistance; lipid; metabolic dysfunction-associated fatty liver disease; oxidative stress.

Figure 1

Mechanisms of lipid metabolism abnormalities in MAFLD and CKD. (A) In MAFLD, DNL enhanced by elevated insulin and glucose levels, FAO overload, and increased FA influx leads to lipid accumulation and steatosis. Excessive energy contributes to TCA mitochondrial dysfunction and ROS production. In turn, oxidative stress inhibits the PGC-1α/CPT-1/FAO axis. PPAR-γ shows opposite expression patterns in the liver and adipose tissue, enhancing hepatic DNL and adipocyte lipolysis, respectively, and exacerbating fat accumulation in MALFD. Increased levels of TG-containing VLDL are released into circulation, together with decreased HDL-c and increased LDL-c levels, which are regulated by increased CETP and inhibited LPL, forming dyslipidemia. (B) In CKD, abnormality of enzymes including LPL, LCAT, and CETP and dysregulated expression of VLDLR, LDLR, and LRP contribute to CKD dyslipidemia, characterized by increased LDL-c levels, elevated VLDL levels, and impaired HDL. Abnormal lipid enzymes in CKD are also related to uremic toxins and dialysis status. Down-regulation of the PGC-1α/CPT-1 pathway in the renal tubules and up-regulation of transporters such as CD36 cause lipid accumulation in the kidneys.

Figure 2

Metabolic dysfunction linking MAFLD and CKD. (MAFLD) and chronic kidney disease (CKD) share a dyslipidemic signature, including decreased HDL-C, elevated LDL-C and VLDL, and altered lipoprotein receptor profiles. Hepatic lipid overload precipitates mitochondrial dysfunction and ROS generation, whereas impaired toxin clearance in renal failure magnifies this oxidative milieu. ROS drive the formation of ALE, ox-LDL, ox-PL, and other pro-inflammatory danger-associated molecular patterns, fostering systemic multi-organ inflammation. Adipose inflammation aggravates insulin resistance and liberates FFAs, accelerating lipid flux to both the liver and kidney, which is ectopic fat accumulation. In the liver, ALEs and CD36-mediated ox-LDL uptake activate resident immune cells and trigger HSC-driven fibrosis. In the kidney, deposition of ox-LDL, FFAs, and other lipoproteins induces macrophage foam-cell formation and promotes glomerulosclerosis and fibrosis.

Figure 3

Cellular mechanism of hepatic and peripheral insulin resistance. Under obesity and systemic inflammation, FA input and cytokine stimulation is increased. FAO/TCA imbalance and mitochondrial dysfunction causes an increase in ROS and lipotoxic products (DAGs and ceramides) of DNL. The inflammatory factor TNF-α activates the NF-κβ/JNK and iNOS-NO pathways, impairing the IRS/Akt/GLUT2/4 insulin signaling pathway; DAG/PKC signals inhibit the insulin receptor, and ceramide induces the iNOS inflammatory pathway and inhibits Akt. Hepatic insulin resistance is selective: Inactivation of the IRS2/AKT/FOXO signaling pathway leads to a decrease in insulin’s ability to inhibit glucose metabolism; due to differences in the intrahepatic expression distribution of IRS-1 and IRS-2, the IRS-1/Akt/mTOR pathway is less affected by PKC signaling, thereby enhancing SREBP-1c/DNL.

Figure 4

Insulin resistance in MAFLD and CKD and the interaction between the two diseases. In NAFLD, lipid overload triggers inflammatory responses and insulin resistance in adipocytes, acting as a pump for the export of FFA/glucose and inflammatory factors. Hepatic insulin resistance can be driven by high-fructose diets, dysregulation of FAO/DNL, and the formation of lipotoxic products, as well as by increased energy input from peripheral tissues. In CKD, HDL immaturity, increase in fructose/uric acid axis, decreased EPO production, and PTH hypersecretion contribute to systemic insulin resistance. CKD and diabetes can both cause HDL immaturity, leading to reduced HDL-c and increased LDL-c levels; meanwhile, MAFLD enhances VLDL output, exacerbating this pattern of dyslipidemia. Increased deposition of lipoproteins (VLDL and LDL-c), FAs, and glucose in the kidneys induces lipotoxicity and inflammatory response, which stimulate gluconeogenesis activation and insulin resistance in the kidneys; insulin resistance in the kidneys exacerbates glomerulosclerosis and renal fibrosis. MAFLD and CKD both exhibit abnormalities in adipokines and hepatokines, which induce systemic insulin resistance; abnormal adipokines cause damage to glomerulus and liver cells. Within the SNS/RAS/ROS axis, insulin, and adipokine, there is a feedback loop amplifying the interactions among them, and then leptin/SNS/RAS axis activates fibrotic signals in the liver and kidneys.

Figure 5

Drugs with verified clinical potential shared by two diseases.