Lipid metabolism

Lipid metabolism US Medical PG Question 1: A 15-year-old boy is brought to the emergency department by his parents because of lethargy, repeated vomiting, and abdominal pain for 6 hours. Over the past 2 weeks, he has reported increased urinary frequency to his parents that they attributed to his increased oral fluid intake. Examination shows dry mucous membranes and rapid, deep breathing. Laboratory studies show the presence of acetoacetate in the urine. Which of the following cells is unable to use this molecule for energy production?

• A. Myocyte
• B. Adipocyte
• C. Neuron
• D. Thrombocyte
• E. Hepatocyte (Correct Answer)

Lipid metabolism Explanation: ***Hepatocyte*** - **Hepatocytes** are the primary site of **ketone body synthesis** during fasting, starvation, or poorly controlled diabetes, producing acetoacetate and β-hydroxybutyrate from fatty acid oxidation. - However, hepatocytes **cannot utilize ketone bodies for energy** because they lack the enzyme **succinyl-CoA:3-ketoacid CoA transferase (thiophorase)**, which is essential for converting acetoacetate to acetoacetyl-CoA. - This enzymatic deficiency ensures that ketone bodies produced by the liver are exported to **peripheral tissues** (brain, muscle, kidney) for energy utilization during periods of glucose scarcity. - This represents a critical metabolic concept: the liver makes ketones for other organs but cannot use them itself. *Thrombocyte* - **Thrombocytes** (platelets) lack **mitochondria** and rely exclusively on **anaerobic glycolysis** for ATP production. - While platelets technically cannot use ketone bodies due to the absence of mitochondria, this is not the primary educational focus when discussing ketone body metabolism in biochemistry. - Platelets also cannot perform oxidative phosphorylation or utilize fatty acids. *Adipocyte* - **Adipocytes** can utilize **acetoacetate** for energy, particularly during fasting states when ketone body levels are elevated. - They possess mitochondria and the enzyme **succinyl-CoA:3-ketoacid CoA transferase**, allowing conversion of acetoacetate to acetoacetyl-CoA and subsequent entry into the citric acid cycle. *Myocyte* - **Myocytes** (cardiac and skeletal muscle) are major consumers of **ketone bodies** during prolonged fasting, starvation, or extended exercise. - The heart preferentially uses ketone bodies over glucose when available, making them highly efficient at ketone body oxidation. - Muscle cells contain all necessary enzymes to convert acetoacetate to acetyl-CoA for **oxidative phosphorylation**. *Neuron* - **Neurons** adapt to use **ketone bodies** as an alternative fuel to glucose during prolonged fasting (after 3-4 days), providing up to 60-70% of the brain's energy needs. - This metabolic flexibility is crucial for survival during starvation and is the basis for therapeutic ketogenic diets in certain neurological conditions. - Brain tissue efficiently metabolizes both acetoacetate and β-hydroxybutyrate.

Lipid metabolism US Medical PG Question 2: A 63-year-old man with high blood pressure, dyslipidemia, and diabetes presents to the clinic for routine follow-up. He has no current complaints and has been compliant with his chronic medications. His blood pressure is 132/87 mm Hg and his pulse is 75/min and regular. On physical examination, you notice that he has xanthelasmas on both of his eyelids. He currently uses a statin to lower his LDL but has not reached the LDL goal you have set for him. You would like to add an additional medication for LDL control. Of the following, which statement regarding fibrates is true?

• A. Fibrates inhibit the rate-limiting step in cholesterol synthesis
• B. Fibrates can potentiate the risk of myositis when given with statins (Correct Answer)
• C. Fibrates can cause significant skin flushing and pruritus
• D. Fibrates can increase the risk of cataracts
• E. The primary effect of fibrates is to lower LDL

Lipid metabolism Explanation: ***Fibrates can potentiate the risk of myositis when given with statins*** - **Fibrates** and **statins** can both independently cause muscle toxicity (myopathy, rhabdomyolysis). - When used concomitantly, especially **gemfibrozil** with statins, there is an **increased risk of muscle adverse events** due to pharmacokinetic interactions that raise statin levels. - This combination requires careful monitoring and is often avoided; **fenofibrate** is preferred over gemfibrozil when combination therapy is needed. *Fibrates inhibit the rate-limiting step in cholesterol synthesis* - This statement describes the mechanism of action of **statins**, which inhibit **HMG-CoA reductase**, the rate-limiting enzyme in cholesterol synthesis. - Fibrates, on the other hand, act primarily by activating **PPAR-alpha receptors**, leading to altered lipid metabolism (increased lipoprotein lipase activity, decreased VLDL synthesis). *Fibrates can cause significant skin flushing and pruritus* - **Niacin (nicotinic acid)** is the lipid-modifying agent most commonly associated with significant **skin flushing and pruritus**, mediated by prostaglandin release. - Fibrates do not cause significant flushing; their side effects include GI disturbances, gallstones, and potential muscle toxicity. *Fibrates can increase the risk of cataracts* - This is **not an established adverse effect** of the fibrate class. - While **clofibrate** (an older, largely discontinued fibrate) showed some association with cataracts in older studies, this is not a recognized risk with modern fibrates like **fenofibrate** and **gemfibrozil**. - Current fibrate therapy does not require routine ophthalmologic monitoring for cataracts. *The primary effect of fibrates is to lower LDL* - The primary effect of **fibrates** is to significantly **lower triglycerides** (by 30-50%) and **increase HDL cholesterol** levels (by 10-20%). - While they can cause a modest decrease in LDL cholesterol (10-15%), this is not their primary or most pronounced lipid-modifying effect. - Fibrates are primarily indicated for **hypertriglyceridemia** and mixed dyslipidemia.

Lipid metabolism US Medical PG Question 3: A 24-year-old man presents for an annual check-up. He is a bodybuilder and tells you he is on a protein-rich diet that only allows for minimal carbohydrate intake. His friend suggests he try exogenous glucagon to help him lose some excess weight before an upcoming competition. Which of the following effects of glucagon is he attempting to exploit?

• A. Increased glucose utilization by tissues
• B. Decreased blood cholesterol level
• C. Increased hepatic gluconeogenesis
• D. Increased lipolysis in adipose tissues (Correct Answer)
• E. Increased hepatic glycogenolysis

Lipid metabolism Explanation: ***Increased lipolysis in adipose tissues*** - While **glucagon's primary target is the liver**, it can have **modest lipolytic effects** on adipose tissue by opposing insulin's anti-lipolytic actions. - Glucagon stimulates cAMP production, which can activate **hormone-sensitive lipase** to break down triglycerides into **fatty acids** and **glycerol**. - However, **catecholamines (epinephrine/norepinephrine)** are far more potent direct stimulators of adipose tissue lipolysis than glucagon. - The friend is attempting to exploit this lipolytic effect for fat loss, though **exogenous glucagon is not an evidence-based or safe weight-loss strategy**. *Increased glucose utilization by tissues* - This is **opposite** to glucagon's actual effect. **Glucagon raises blood glucose** levels; it does not promote glucose uptake by peripheral tissues. - **Insulin** is the hormone responsible for promoting glucose uptake and utilization by muscle, adipose, and other tissues. *Decreased blood cholesterol level* - Glucagon does not have a direct, clinically significant effect on reducing blood cholesterol levels. - While glucagon affects overall lipid metabolism through its catabolic actions, it is not used therapeutically for hypercholesterolemia. *Increased hepatic gluconeogenesis* - **Glucagon strongly stimulates hepatic gluconeogenesis**, which is the synthesis of glucose from non-carbohydrate precursors (amino acids, lactate, glycerol) in the liver. - This action **raises blood glucose** levels and would not directly contribute to fat loss or weight reduction. - In the context of a low-carbohydrate diet, increased gluconeogenesis would maintain blood glucose but not promote the fat loss the bodybuilder seeks. *Increased hepatic glycogenolysis* - **Glucagon is a potent stimulator of hepatic glycogenolysis**, the breakdown of stored liver glycogen into glucose. - This rapidly increases blood glucose levels during fasting or hypoglycemia. - However, this does not directly target adipose tissue for fat loss; it mobilizes glucose stores rather than fat stores, so it's not the mechanism relevant to weight loss goals.

Lipid metabolism US Medical PG Question 4: A 57-year-old man presents to his family physician for a checkup. He has had type 2 diabetes mellitus for 13 years, for which he has been taking metformin and vildagliptin. He has smoked 10–15 cigarettes daily for 29 years. Family history is irrelevant. Vital signs include: temperature 36.6°C (97.8°F), blood pressure 152/87 mm Hg and pulse 88/min. Examination reveals moderate abdominal obesity with a body mass index of 32 kg/m². The remainder of the examination is unremarkable. His fasting lipid profile is shown: Total cholesterol (TC) 280 mg/dL Low-density lipoprotein (LDL)-cholesterol 210 mg/dL High-density lipoprotein (HDL)-cholesterol 40 mg/dL Triglycerides (TGs) 230 mg/dL Which of the following is the mechanism of action of the best initial therapy for this patient?

• A. Activation of PPAR-alpha
• B. Inhibition of cholesterol absorption
• C. Bile acid sequestration
• D. Inhibition of cholesterol synthesis (Correct Answer)
• E. Inhibition of adipose tissue lipolysis

Lipid metabolism Explanation: ***Inhibition of cholesterol synthesis*** - This patient has multiple risk factors for cardiovascular disease including **type 2 diabetes**, **hypertension**, **smoking**, and significantly **elevated LDL-cholesterol (210 mg/dL)**, making him a candidate for high-intensity statin therapy. - **Statins** (HMG-CoA reductase inhibitors) are the first-line therapy for such patients as they significantly reduce cardiovascular events by **inhibiting the rate-limiting step in cholesterol synthesis** in the liver. *Activation of PPAR-alpha* - This is the mechanism of action of **fibrates** (e.g., fenofibrate, gemfibrozil), which are primarily used to **lower triglycerides** and raise HDL-cholesterol. - While this patient has elevated triglycerides, his primary lipid abnormality and cardiovascular risk comes from his high LDL-cholesterol, making statins the better initial choice. *Inhibition of cholesterol absorption* - This describes the mechanism of action of **ezetimibe**, which selectively inhibits cholesterol absorption at the brush border of the small intestine. - Ezetimibe is typically used as an add-on therapy if statins alone are insufficient to reach LDL-C goals, or if a patient is statin-intolerant, not as a monotherapy for high-risk patients. *Bile acid sequestration* - This is the mechanism of **bile acid resins** (e.g., cholestyramine, colestipol, colesevelam), which bind bile acids in the intestine, preventing their reabsorption and increasing their excretion. - This leads to increased hepatic synthesis of bile acids from cholesterol, thereby upregulating LDL receptors and lowering LDL-cholesterol, but they are less potent than statins and can cause gastrointestinal side effects. *Inhibition of adipose tissue lipolysis* - This is the mechanism of action of **niacin (nicotinic acid)**, which reduces the synthesis of VLDL and LDL by inhibiting lipolysis in adipose tissue. - Niacin can improve all lipid parameters but is often associated with significant side effects (e.g., flushing, insulin resistance) and has not consistently shown cardiovascular benefit beyond statins in recent trials, making it a less preferred initial therapy.

Lipid metabolism US Medical PG Question 5: A 50-year-old man comes to the physician for his annual health maintenance examination. The patient feels well. He has a history of hypertension, for which he currently takes lisinopril. He has smoked a pack of cigarettes daily for 20 years. He drinks 5–6 beers on weekends. He is 181 cm tall (5 ft 11 in), weighs 80 kg (176.4 lbs); BMI is 24.6 kg/m2. His pulse is 75/min, blood pressure is 140/85 mm Hg, and respirations are 18/min. Physical examination is unremarkable. Laboratory studies show: Total cholesterol 263 mg/dL High-density lipoprotein cholesterol 36 mg/dL Triglycerides 180 mg/dL In addition to dietary and lifestyle modification, administration of which of the following agents is the most appropriate next step in management?

• A. Peroxisome proliferator-activated receptor alpha activator
• B. Proprotein convertase subtilisin kexin 9 inhibitor
• C. Bile acid resins
• D. HMG-CoA reductase inhibitor (Correct Answer)
• E. Cholesterol absorption inhibitor

Lipid metabolism Explanation: ***HMG-CoA reductase inhibitor*** - This patient has multiple **cardiovascular risk factors** (hypertension, smoking, low HDL, elevated LDL-c calculated from total cholesterol and triglycerides) and elevated LDL-c. An **HMG-CoA reductase inhibitor (statin)** is the first-line pharmacotherapy in such cases to reduce the risk of atherosclerotic cardiovascular disease events. - Statins effectively lower **LDL-c**, which is the primary target for cholesterol reduction in patients at high risk for cardiovascular disease. *Peroxisome proliferator-activated receptor alpha activator* - **Fibrates** (PPAR-α activators) are primarily used to lower **triglycerides** and increase HDL, and are not the first-line choice for lowering elevated LDL-c in high-risk patients. - They are typically reserved for severe hypertriglyceridemia not controlled by statins, or in patients intolerant to statins whose primary lipid issue is hypertriglyceridemia. *Proprotein convertase subtilisin kexin 9 inhibitor* - **PCSK9 inhibitors** are potent LDL-c lowering agents, but they are typically used as **adjunctive therapy** in patients with high cardiovascular risk who have not achieved adequate LDL-c reduction with maximum tolerated statin therapy, or in patients with familial hypercholesterolemia. - Given that this patient has not yet started statin therapy, a PCSK9 inhibitor is not the initial treatment strategy. *Bile acid resins* - **Bile acid resins** (e.g., cholestyramine) lower LDL-c by binding to bile acids in the intestine, but they are **less effective** than statins and can sometimes increase triglycerides. - They are generally not the first-line choice for primary LDL-c reduction due to their side effect profile (e.g., GI upset) and lower efficacy compared to statins. *Cholesterol absorption inhibitor* - **Ezetimibe** (a cholesterol absorption inhibitor) reduces cholesterol absorption in the small intestine, leading to lower LDL-c. - It is often used as an **add-on therapy** to statins or as monotherapy in statin-intolerant patients, but not as the initial drug of choice when a statin is indicated and tolerated.

Lipid metabolism US Medical PG Question 6: A 58-year-old woman presents to the physician for a routine health maintenance examination. She has a history of dyslipidemia and chronic hypertension. Her medications include atorvastatin, hydrochlorothiazide, and lisinopril. She exercises every day and follows a healthy diet. She does not smoke. There is no family history of chronic disease. Her blood pressure is 130/80 mm Hg, which is confirmed on repeat measurement. Her BMI is 22 kg/m2. The physical examination shows no abnormal findings. The laboratory test results show: Serum Total cholesterol 193 mg/dL Low-density lipoprotein (LDL-C) 124 mg/dL High-density lipoprotein (HDL-C) 40 mg/dL Triglycerides 148 mg/dL The patient's 10-year risk of cardiovascular disease (CVD) is 4.6%. Which of the following is the most appropriate next step in pharmacotherapy?

• A. Fish oils
• B. No additional pharmacotherapy at this time
• C. Niacin
• D. Fenofibrate
• E. Ezetimibe (Correct Answer)

Lipid metabolism Explanation: ***Ezetimibe*** - The patient has an **LDL-C of 124 mg/dL** despite being on atorvastatin. According to the 2018 AHA/ACC guidelines, adding **ezetimibe** to a statin is recommended when LDL-C remains elevated (>70 mg/dL secondary prevention, >100 mg/dL primary prevention with high ASCVD risk) after maximally tolerated statin therapy to further reduce cardiovascular risk. - Adding **ezetimibe** to atorvastatin would help further lower her LDL-C levels, which is crucial given her dyslipidemia and hypertension, despite her overall healthy lifestyle. *Fish oils* - **Fish oils**, specifically high-dose omega-3 fatty acids, are primarily considered for patients with **severe hypertriglyceridemia** (>500 mg/dL) or those with elevated triglycerides (135-499 mg/dL) despite statin therapy and elevated cardiovascular risk, particularly if their HDL-C is low and they have established CVD. - While this patient has mild hypertriglyceridemia (148 mg/dL) and low HDL-C, her primary concern for further intervention is her elevated LDL-C, making ezetimibe a more appropriate first-line additive. *No additional pharmacotherapy at this time* - While the patient has a relatively low 10-year CVD risk (4.6%) and healthy lifestyle, her **LDL-C of 124 mg/dL** remains elevated despite atorvastatin. This level, in conjunction with her history of dyslipidemia and hypertension, warrants further intervention to reduce her lifetime ASCVD risk. - Given her established risk factors, maintaining an elevated LDL-C when further reduction is achievable through safe and effective pharmacotherapy is not ideal for long-term cardiovascular health. *Niacin* - **Niacin** can lower LDL-C and triglycerides while increasing HDL-C, but multiple clinical trials have failed to show a consistent benefit in reducing cardiovascular events when added to statin therapy, often due to significant side effects (e.g., flushing, insulin resistance, hepatotoxicity). - Its use has largely declined in favor of other agents due to unfavorable risk-benefit profiles in combination with statins. *Fenofibrate* - **Fenofibrate** is primarily used to treat **hypertriglyceridemia** and can also raise HDL-C, but it has not consistently shown benefit in reducing cardiovascular outcomes when added to statins in patients with mild-to-moderate hypertriglyceridemia. - While her triglycerides are slightly elevated, her primary lipid target for further management remains LDL-C reduction.

Lipid metabolism US Medical PG Question 7: A 12-year-old girl comes to the clinic with a grossly enlarged abdomen. She has a history of frequent episodes of weakness, sweating, and pallor that are eliminated by eating. Her development has been slow. She started to walk unassisted at 2 years and was not performing well at school. Physical examination reveals a blood pressure of 100/60 mm Hg, heart rate of 80/min, and temperature of 36.9°C (98.4℉). On physical examination, the liver is enlarged, firm, and palpable up to the pelvis. The spleen and kidney are not palpable. Laboratory investigation reveals low blood glucose and pH with high lactate, triglycerides, ketones, and free fatty acids. The liver biopsy revealed high glycogen content. Hepatic glycogen structure was normal. The enzyme assay performed on the biopsy tissue revealed very low glucose-6-phosphatase levels. What is the most likely diagnosis?

• A. Pompe's disease
• B. Cori's disease
• C. Hereditary hemochromatosis
• D. Von-Gierke's disease (Correct Answer)
• E. McArdle disease

Lipid metabolism Explanation: ***Von-Gierke's disease*** - The combination of **hepatomegaly**, **hypoglycemia** (causing weakness, sweating, pallor), **lactic acidosis**, **hyperlipidemia**, and elevated ketones points to a severe defect in glucose metabolism. - **Very low glucose-6-phosphatase levels** on liver biopsy and normal hepatic glycogen structure are pathognomonic for Von-Gierke's disease (Glycogen Storage Disease Type I). *Pompe's disease* - This is a **lysosomal storage disease** affecting **alpha-1,4-glucosidase**, leading to glycogen accumulation in lysosomes. - It primarily affects the **heart** and skeletal muscles and would not present with severe lactic acidosis and hyperlipidemia. *Cori's disease* - This is **Glycogen Storage Disease Type III**, caused by a deficiency in the **debranching enzyme** (amylo-alpha-1,6-glucosidase). - While it can cause hepatomegaly and hypoglycemia, the hepatic glycogen structure would be abnormal due to incompletely debranched glycogen, and glucose-6-phosphatase levels would be normal. *Hereditary hemochromatosis* - This is an **iron overload disorder** leading to iron deposition in organs like the liver, heart, and pancreas. - It would present with symptoms related to organ damage from iron accumulation, such as liver cirrhosis and diabetes, not the metabolic derangements seen here. *McArdle disease* - This is **Glycogen Storage Disease Type V**, due to a deficiency in **muscle glycogen phosphorylase**. - It primarily causes exercise-induced muscle pain, cramping, and fatigue due to an inability to break down muscle glycogen for energy, not systemic metabolic disturbances or hepatomegaly.

Lipid metabolism US Medical PG Question 8: A 5-month-old boy presents with increasing weakness for the past 3 months. The patient’s mother says that the weakness is accompanied by dizziness, sweating, and vertigo early in the morning. Physical examination shows hepatomegaly. Laboratory findings show an increased amount of lactate, uric acid, and elevated triglyceride levels. Which of the following enzymes is most likely deficient in this patient?

• A. Hepatic glycogen phosphorylase
• B. Debranching enzyme
• C. Glucose-6-phosphatase (Correct Answer)
• D. Muscle glycogen phosphorylase
• E. Lysosomal α-1,4-glucosidase

Lipid metabolism Explanation: ***Glucose-6-phosphatase*** - The constellation of **hypoglycemia** (weakness, dizziness, sweating, vertigo, especially early morning), **hepatomegaly**, **lactic acidosis**, **hyperuricemia**, and **hypertriglyceridemia** are classic features of **Type I glycogen storage disease (von Gierke disease)**, which is caused by a deficiency of **glucose-6-phosphatase**. - This enzyme is crucial for the final step of both **glycogenolysis** and **gluconeogenesis**, releasing free glucose into the bloodstream; its deficiency leads to an inability to maintain normal blood glucose levels during fasting and accumulation of glucose-6-phosphate, which shunts into other metabolic pathways. *Hepatic glycogen phosphorylase* - Deficiency in **hepatic glycogen phosphorylase** (Type VI glycogen storage disease, Hers disease) would cause **hepatomegaly** and **hypoglycemia**, but typically does not present with severe **lactic acidosis**, **hyperuricemia**, or **hypertriglyceridemia** to the same degree as von Gierke disease. - The primary defect is in breaking down glycogen, leading to its accumulation in the liver, but the products of glycolysis can still exit the liver via gluconeogenesis. *Debranching enzyme* - Deficiency in **debranching enzyme** (Type III glycogen storage disease, Cori or Forbes disease) causes **hepatomegaly** and **hypoglycemia**, but usually presents with milder symptoms and less severe **lactic acidosis**, **hyperuricemia**, and **hypertriglyceridemia**. - Patients often present with symptoms similar to Type I, but muscle involvement is also common, and **glycogen structures with short outer branches** are characteristic. *Muscle glycogen phosphorylase* - Deficiency in **muscle glycogen phosphorylase** (Type V glycogen storage disease, McArdle disease) primarily affects **skeletal muscle**, leading to exercise intolerance, muscle pain, and myoglobinuria. - It does not typically cause **hypoglycemia** or **hepatomegaly**, as the liver enzyme is functional, and the symptoms described are systemic rather than muscle-specific. *Lysosomal α-1,4-glucosidase* - Deficiency in **lysosomal α-1,4-glucosidase** (Type II glycogen storage disease, Pompe disease) primarily affects the **heart, muscle, and liver**, causing severe **cardiomyopathy**, hypotonia, and **hepatomegaly**. - While it involves glycogen accumulation, it typically does not present with **hypoglycemia** (as cytoplasmic glycogen metabolism is intact), **lactic acidosis**, or the specific metabolic derangements seen in this patient.

Lipid metabolism US Medical PG Question 9: A 12-year-old boy is brought to the physician because of difficulty in walking for 5 months. His mother reports that he has trouble keeping his balance and walking without support. Over the past year, he has started to have difficulty seeing in the dark and his hearing has been impaired. Examination shows marked scaling of the skin on the face and feet and a shortened 4th toe. Muscle strength is 3/5 in the lower extremities and 4/5 in the upper extremities. Sensation to pinprick is symmetrically decreased over the legs. Fundoscopy shows peripheral pigment deposits and retinal atrophy. His serum phytanic acid concentration is markedly elevated. The patient's condition is most likely caused by a defect in which of the following cellular structures?

• A. Proteasomes
• B. Peroxisomes (Correct Answer)
• C. Smooth endoplasmic reticulum
• D. Mitochondria
• E. Myofilaments

Lipid metabolism Explanation: ***Peroxisomes*** - The constellation of symptoms including **difficulty walking and maintaining balance**, **impaired night vision and hearing**, **scaling skin**, **distal muscle weakness**, **ataxia**, **peripheral neuropathy**, **pigmentary retinopathy**, and **markedly elevated serum phytanic acid** is characteristic of **Refsum disease**. - **Refsum disease** is an autosomal recessive disorder caused by a defect in **peroxisomal alpha-oxidation** (specifically phytanoyl-CoA hydroxylase deficiency), leading to the accumulation of phytanic acid in tissues. - Phytanic acid is a branched-chain fatty acid derived from dietary sources (dairy products, ruminant fats) that cannot undergo beta-oxidation and requires alpha-oxidation in peroxisomes. *Proteasomes* - **Proteasomes** are responsible for the degradation of ubiquitinated proteins, important for cellular protein homeostasis. - Defects in proteasomes are associated with various conditions like **neurodegenerative diseases** (e.g., Parkinson's), but not with the specific symptoms of phytanic acid accumulation. *Smooth endoplasmic reticulum* - The **smooth endoplasmic reticulum** is involved in **lipid synthesis**, detoxification, and calcium storage. - While lipid metabolism is affected in Refsum disease, the primary defect is in the degradation of branched-chain fatty acids like phytanic acid, which occurs in **peroxisomes**, not the smooth ER. *Mitochondria* - **Mitochondria** are the primary sites of **ATP production** through oxidative phosphorylation and are involved in fatty acid beta-oxidation. - While some metabolic disorders affect mitochondria, **phytanic acid accumulation** specifically points to a peroxisomal defect because phytanic acid cannot undergo beta-oxidation due to its 3-methyl branch and requires alpha-oxidation, which is a peroxisomal process. *Myofilaments* - **Myofilaments** (actin and myosin) are the contractile proteins within muscle cells. - While muscle weakness is a symptom, the underlying cause is not a primary defect in myofilaments themselves, but rather the **neurological and systemic effects** of phytanic acid accumulation affecting peripheral nerves and muscle innervation.

Lipid metabolism US Medical PG Question 10: A 34-year-old male visits the clinic with complaints of intermittent diarrhea over the past 6 months. He has lost 6.8 kg (15 lb) over that time period. His frequent bowel movements are affecting his social life and he would like definitive treatment. Past medical history is significant for chronic type 2 diabetes that is well controlled with insulin. No other family member has a similar condition. He does not smoke tobacco and drinks alcohol only on weekends. Today, his vitals are within normal limits. On physical exam, he appears gaunt and anxious. His heart has a regular rate and rhythm and his lungs are clear to auscultation bilaterally. Additionally, the patient has a red-purple rash on his lower abdomen, groin, and the dorsum of both hands. The rash consists of pruritic annular lesions. He is referred to a dermatologist for core biopsy which is consistent with necrolytic migratory erythema. Further workup reveals a large hormone secreting mass in the tail of his pancreas. Which of the following is the action of the hormone that is in excess in this patient?

• A. Activation of glycogen synthase
• B. Inhibition of gluconeogenesis
• C. Inhibition of insulin secretion
• D. Stimulation of lipolysis (Correct Answer)
• E. Inhibition of acetone production

Lipid metabolism Explanation: ***Stimulation of lipolysis*** - The patient's symptoms (diarrhea, weight loss, necrolytic migratory erythema, and a pancreatic mass) are highly suggestive of a **glucagonoma**. - **Glucagon** is a catabolic hormone that **stimulates gluconeogenesis and glycogenolysis** to raise blood glucose, and it also promotes **lipolysis** and **ketogenesis**. *Activation of glycogen synthase* - **Glycogen synthase** is activated by **insulin**, which promotes glycogen synthesis, storing glucose. - Glucagon opposes the action of insulin; thus, it would **inactivate glycogen synthase**, not activate it. *Inhibition of gluconeogenesis* - **Glucagon's primary role** is to increase blood glucose levels, and it does so by **stimulating gluconeogenesis and glycogenolysis**. - **Inhibition of gluconeogenesis** would occur with insulin, not glucagon. *Inhibition of insulin secretion* - While glucagon can have complex effects on insulin, its primary metabolic actions are independent of direct inhibition of insulin secretion. - Pancreatic somatostatin inhibits both insulin and glucagon secretion. *Inhibition of acetone production* - Glucagon promotes **ketogenesis**, which can lead to the production of **ketone bodies**, including acetone, especially in states of insulin deficiency. - Therefore, glucagon would **stimulate**, not inhibit, processes that can lead to acetone production.

Lipid metabolism Flashcard 1 of 10

Question: Kwashiorkor may present as liver malfunction with fatty change due to decreased _____ synthesis

Answer: apolipoprotein

Lipid metabolism Flashcard 2 of 10

Question: The triglycerides inside the VLDL are broken down into _____ by lipoprotein lipase in the vicinity of the adipocytes (or peripheral tissue)

Answer: fatty acids

Lipid metabolism Flashcard 3 of 10

Question: Ketogenesis begins with _____, which is provided by -oxidation of fatty acids

Answer: acetyl-CoA

Lipid metabolism Flashcard 4 of 10

Question: What is the rate-limiting enzyme for cholesterol synthesis?_____

Answer: HMG CoA reductase

Lipid metabolism Flashcard 5 of 10

Question: Which serum lipids (2) are elevated in type I hyperlipoproteinemia? _____

Answer: Triglycerides and cholesterol

Lipid metabolism Flashcard 6 of 10

Question: Dyslipidemia drugs _____ HDL particles contain LCAT-generated cholesterol esters

Answer: Mature

Lipid metabolism Flashcard 7 of 10

Question: Glucocorticoids increase peripheral _____, which provides more glycerol to the liver for gluconeogenesis

Answer: lipolysis

Lipid metabolism Flashcard 8 of 10

Question: Cholesterol synthesis begins with _____

Answer: acetyl CoA

Lipid metabolism Flashcard 9 of 10

Question: lipoamide

Answer: acyl groups

Lipid metabolism Flashcard 10 of 10

Question: Where does fatty acid oxidation take place?

Answer: mitochondria